JP2012532170A - Indazolyl-substituted dihydroisoxazolopyridine and method of use - Google Patents

Abstract

  The present invention relates to a novel 4- (indazol-5-yl) -4,7-dihydroisoxazolo [5,4-b] pyridine derivative having protein tyrosine kinase inhibitory activity, a method for producing the same, and a c-Met-mediated disease or It relates to its use for treating c-Met mediated symptoms, in particular cancer and other proliferative disorders.

Description

  The present invention relates to a novel 4- (indazol-5-yl) -4,7-dihydroisoxazolo [5,4-b] pyridine derivative having protein tyrosine kinase inhibitory activity, a method for producing the same, and a c-Met mediated disease Or its use to treat c-Met mediated symptoms, particularly cancer and other proliferative disorders.

  Cancer is one of the most common widespread diseases. In 2002, over 4.4 million people worldwide were diagnosed with breast cancer, colon cancer, ovarian cancer, lung cancer or prostate cancer, and over 2.5 million people were no longer caused by these serious illnesses ( Globocan 2002 Report, http://www-dep.iarc.fr/globocan/downloads.htm). In the United States alone, more than 1.25 million people were newly diagnosed with cancer in 2005 and more than 500,000 people were expected to die. Most of these newly diagnosed patients were thought to be colorectal cancer (about 100,000), lung cancer (about 170,000), breast cancer (about 210,000) and prostate cancer (about 230,000). Assuming an average rate of increase of 1.4%, both the incidence and prevalence of cancer are expected to increase by about 15% over the next decade (American Cancer Society, Cancer Facts and Figures 2005; http //Www.cancer.org/docroot/STT/content/STT_1 x_Cancer_Facts_Figures_2007.asp).

  There are many pathways for how cancer can develop, which is one reason why it is difficult to treat cancer. One pathway is the transformation of cells by oncoproteins derived from normal cellular proteins by genetic variation, which results in non-physiological activation of these proteins. One family of proteins from which many oncoproteins are derived are tyrosine kinases (eg, src kinase), particularly receptor tyrosine kinases (RTK). In the past 20 years, numerous studies have revealed the importance of receptor tyrosine kinase (RTK) -mediated signaling in the control of mammalian cell growth. More recently, results have been obtained in clinical trials using selective small molecule inhibitors of tyrosine kinases as antitumor agents.

  The c-Met receptor is also a receptor tyrosine kinase. The possibility of carcinogenesis in the early 1980s when mutated Met was isolated from a chemically derived human osteosarcoma cell line with the kinase domain of the Met gene fused to the dimerization domain at its N-terminus. [CS Cooper et al., Nature 311: 29-33 (1984)].

  Cellular Met protein is a heterodimeric transmembrane protein synthesized as a single-chain 190 kd precursor [G.A. Rodrigues et al., Mol. Cell Biol. 11: 2962-70 (1991)]. The precursor is cleaved intracellularly after amino acid residue 307 to form a 50 kd α chain and a 145 kd β chain, which are linked by a disulfide bond. The α chain is completely extracellular, whereas the β chain extends to the cell membrane. The β chain consists of an N-terminal sema domain and mediates ligand binding together with the α chain. The remainder of the intracellular domain of the β chain consists of a cysteine-rich domain and four immunoglobulin domains, followed by a transmembrane region and an intracellular domain. The intracellular domain contains a near-membrane domain, a kinase domain, and a C-terminal domain, which mediates downstream signaling. Binding of the ligand induces receptor dimerization, and a series of tyrosine autophosphorylation steps in the near membrane region (Y1003), the kinase activation loop (Y1234 and Y1235) and the carboxy-terminal domain (Y1349 and Y1356) The kinase domain is activated. Phosphorylated Y1349 and Y1356 contain multiple substrate docking sites for binding adapter proteins required for downstream c-Met signaling [C. Ponzetto et al., Cell 77: 261-71 (1994). ]]. One of the most important substrates for c-Met signaling is the scaffold adapter protein Gab1, which is either Y1349 or Y1356 via an uncommon phospho-tyrosine binding site (called mbs: met binding site) And elicit a unique long-term intracellular signal. Another important substrate is the adapter protein Crb2. Depending on the cellular context, these adapters mediate activation of various intracellular signaling pathways as well as signaling through ERK / MAPK, P13K / Akt, Ras, JNK, STAT, TFκB and β-catenin.

  c-Met is independently activated by hepatocyte growth factor (HGF) (also known as dispersal factor) and its only known biologically active ligand, its splice variant. [L. Naldini et al., Oncogene 6: 501-4 (1991)]. HGF has a unique structure showing similarity to plasminogen family proteinases. It consists of an amino terminal domain followed by four kringle domains and a serine protease homology domain and is not enzymatically active. Similar to c-Met, HGF is synthesized as an inactive single chain precursor (pro-HGF), cleaved extracellularly by serine proteases (eg, plasminogen activator and coagulation factor), and disulfide-bonded α- and β -Converted to a heterodimer of chains. HGF binds to heparan sulfate proteoglycans with high affinity, primarily maintains binding to the extracellular matrix and limits its diffusion. Crystal structure analysis indicates that when bound to c-Met, HGF forms a dimer that induces receptor dimerization.

  HGF is expressed in mesenchymal cells, and in particular by binding to c-Met expressed extensively in epithelial cells, a pleiotropic expression effect is obtained in various tissues including epithelium, endothelium, nerves and hematopoietic cells. The effect is generally due to one or all of the following phenomena: i) stimulation of mitogenesis; HGF was identified by its mitogenic activity in hepatocytes; ii) stimulation of invasion and migration; HGF has been identified as a dispersal factor based on its induction of cell motility (“dispersion”); and iii) stimulation of morphogenesis (tube formation). HGF induces the formation of tubules branched from canine kidney cells in the collagen matrix. Furthermore, evidence from genetically modified mice and from cell culture experiments indicates that c-Met acts as a survival receptor and protects cells from apoptosis [N. Tomita et al., Circulation 107: 1411-1417 (2003); S. Ding et al., Blood 101: 4816-4822 (2003); Q. Zeng et al., J. Biol. Chem. 277: 25203-25208 (2002); N. Horiguchi et al., Oncogene 21: 1791-1799 (2002); A. Bardelli et al., Embo J. 15: 6205-6212 (1996); P. Longati et al., Cell Death Differ. 3: 23-28 (1996); EM Rosen, Symp. Soc. Exp. Biol. 47: 227-234 (1993)]. The coordinated performance of these biological methods by HGF results in a specific genetic program, also called “invasive growth”.

  Under normal conditions, c-Met and HGF are essential for the development of mouse embryos, in particular for the development of the placenta and liver, and for the unidirectional migration of myoblasts from the leg segment. Genetic disruption of the c-Met or HGF gene results in the same phenotype showing its unique interaction. Although the physiological role of c-Met / HGF in adults is not well understood, experimental results suggest that they are involved in wound healing, tissue regeneration, hematopoiesis and tissue homeostasis.

  The identification of the oncoprotein TPR-MET was the first hint that c-Met may play a role in tumorigenesis. Additional substantial evidence is derived from many different experimental methods. Overexpression of c-Met or HGF in human and murine cell lines induces tumorigenesis and metastatic phenotypes when expressed in nude mice. Transgenic overexpression of c-Met or HGF induces tumor formation in mice.

  Most interestingly, c-Met missense mutations or receptor activating mutations are found in sporadic and hereditary papillary renal cell carcinoma (HPRC), as well as lung cancer, stomach cancer, liver cancer, head and neck cancer, ovary Identified in other cancer types such as cancer and brain cancer. Specific c-Met mutations in the HPRC family distinguish a disease that forms a causal relationship between c-Met activation and human cancer [L. Schmidt et al., Nat. Genet. 16: 68-73 (1997); B. Zbar et al., Adv. Cancer Res. 75: 163-201 (1998)]. The activating mutation with the strongest transforming activity is in the activation loop (D1228N / H and Y1280H / D / C) and the adjacent P + 1 loop (M1250T). An additional weaker mutation was found in the A lobe of the kinase domain, near the catalytic loop. Furthermore, mutations in the near-membrane domain of c-Met stabilize the protein without directly activating the kinase, but rather ubiquitination of the kinase, making it resistant to subsequent denaturation, Observed in lung tumors [M. Kong-Beltran et al., Cancer Res. 66: 283-9 (2006); TE Taher et al., J. Immunol. 169: 3793-800 (2002); P. Peschard et al., Mol. Cell 8: 995-1004 (2001)]. Interestingly, c-Met somatic mutations are associated with increased malignant intensity and widespread metastasis in various cancers. Although the frequency of germline and somatic mutations was low (less than 5%), another major mechanism was observed that resulted in deregulation of c-Met signaling without mutation by the paracrine or autocrine mechanism. Activation of paracrine in tumors derived from mesenchymal cells such as osteosarcoma or rhabdomyosarcoma that produce physiological HGF, and in glioblastoma and breast cancer originating from ectoderm, Observed.

  However, the most frequent case is a carcinoma overexpressed c-Met, as observed in carcinomas of the large intestine, pancreas, stomach, prostate, ovary and liver. As observed in gastric and lung cancer cell lines, gene amplification may cause overexpression. More recently, c-Met overexpression was detected in lung tumor cell lines that acquired resistance to EGF receptor inhibition [J.A. Engelmann et al., Science 316: 1039-1043 (2007)]. Certain epithelial cell tumors that overexpress c-Met also express HGF together, resulting in an autocrine c-Met / HGF stimulation loop, thereby avoiding the need for somatic cell-derived HGF.

  In general, abnormal activation of c-Met in human cancers is typically associated with poor prognosis regardless of specific mechanisms [JG Christensen et al., Cancer Lett. 225: 1-26 (2005). ].

  In summary, a number of in vitro and in vivo experiments have been conducted to validate c-Met as an important cancer target, http://www.vai.org/met [C. Birchmeier et al., Nat. Rev. Mol. Cell Biol. 4: 915-25 (2003)]. Several strategies have been followed to attenuate abnormal Met signaling in human tumors, including HPF antagonists and small molecule inhibitors. Many of the small molecule inhibitors such as ARQ-197 (Arqule), XL-880 (Exelixis) and PH-2341066 (Pfizer) are currently in clinical development; recently reported [JJ Cui Expert Opin. Ther. Patents 17: 1035-45 (2007)].

  Therefore, the technical problem to be solved of the present invention is to provide another compound having inhibitory activity against c-Met kinase, and thus to treat c-Met mediated diseases, particularly cancer and other proliferative disorders. To present new treatment options.

  4,7-Dihydroisoxazolo [5,4-b] pyridine as a calcium antagonist having antihypertensive activity is disclosed in JP-A-2040385-Q [CAS Document-No. 113: 40675]. In WO 01 / 66544-A2, tricyclic 3-oxo-1,3,4,7-tetrahydroisoxazolo [3,4-b] pyridine derivatives are useful for the treatment of urogenital diseases and other diseases It is described as a potassium channel opener. Recently, WO 2009 / 006580-A1 claims a heteroaryl fused dihydropyridine that acts as a late sodium channel blocker and its use for treating cardiovascular disorders. A specific 1,4-dihydropyridine derivative having c-Met kinase inhibitory activity is disclosed in WO2008 / 071451-A1.

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［式中
Ｒ^１は、水素、クロロ、ブロモ、（Ｃ_１−Ｃ_６）−アルキル、（Ｃ_３−Ｃ_７）−シクロアルキルおよびフェニルからなる群より選択され、ここで
（ｉ）該（Ｃ_３−Ｃ_７）−シクロアルキルおよびフェニルは、フルオロ、クロロ、ブロモ、ジフルオロメチル、トリフルオロメチル、（Ｃ_１−Ｃ_４）−アルキル、ヒドロキシ、ジフルオロメトキシ、トリフルオロメトキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノ、ジ−（Ｃ_１−Ｃ_４）−アルキルアミノ、（Ｃ_３−Ｃ_６）−シクロアルキルおよび４−ないし６−員のヘテロシクロアルキルからなる群より独立して選択される１または２個の置換基で所望により置換されていてもよく、
ここで、該（Ｃ_１−Ｃ_４）−アルキル、（Ｃ_１−Ｃ_４）−アルコキシ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノおよびジ−（Ｃ_１−Ｃ_４）−アルキルアミノ置換基のアルキル基は、同様に、ヒドロキシまたは（Ｃ_１−Ｃ_４）−アルコキシで所望により置換されていてもよく、および
（ｉｉ）該（Ｃ_１−Ｃ_６）−アルキルは、フルオロ、トリフルオロメチル、ヒドロキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノ、ジ−（Ｃ_１−Ｃ_４）−アルキルアミノ、（Ｃ_３−Ｃ_７）−シクロアルキル、フェニル、４−ないし７−員のヘテロシクロアルキルおよび５−または６−員のヘテロアリールからなる群より独立して選択される１、２または３個の置換基で所望により置換されていてもよく、
ここで該（Ｃ_３−Ｃ_７）−シクロアルキル、フェニル、４−ないし７−員のヘテロシクロアルキルおよび５−または６−員のヘテロアリール置換基は、同様に、フルオロ、クロロ、ブロモ、ジフルオロメチル、トリフルオロメチル、（Ｃ_１−Ｃ_４）−アルキル、オキソ、ヒドロキシ、ジフルオロメトキシ、トリフルオロメトキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノおよびジ−（Ｃ_１−Ｃ_４）−アルキルアミノからなる群より独立して選択される１または２個の残基で所望により置換されていてもよく、または
Ｒ^１は式−ＮＲ^６ＡＲ^６Ｂまたは−ＯＲ^７で示される基であり、ここで
Ｒ^６ＡおよびＲ^６Ｂは、水素、（Ｃ_１−Ｃ_６）−アルキル、（Ｃ_３−Ｃ_７）−シクロアルキルおよび４−ないし７−員のヘテロシクロアルキルからなる群より独立して選択され、ここで
（ｉ）該（Ｃ_３−Ｃ_７）−シクロアルキルおよび４−ないし７−員のヘテロシクロアルキルは、フルオロ、ジフルオロメチル、トリフルオロメチル、（Ｃ_１−Ｃ_４）−アルキル、オキソ、ヒドロキシ、ジフルオロメトキシ、トリフルオロメトキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノおよびジ−（Ｃ_１−Ｃ_４）−アルキルアミノからなる群より独立して選択される１または２個の置換基で所望により置換されていてもよく、および
（ｉｉ）該（Ｃ_１−Ｃ_６）−アルキルは、フルオロ、トリフルオロメチル、ヒドロキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノ、ジ−（Ｃ_１−Ｃ_４）−アルキルアミノ、（Ｃ_３−Ｃ_７）−シクロアルキル、フェニル、４−ないし７−員のヘテロシクロアルキルおよび５−または６−員のヘテロアリールからなる群より独立して選択される１、２または３個の置換基で所望により置換されていてもよく、
ここで、該（Ｃ_３−Ｃ_７）−シクロアルキル、フェニル、４−ないし７−員のヘテロシクロアルキルおよび５−または６−員のヘテロアリール置換基は、同様に、フルオロ、クロロ、ブロモ、ジフルオロメチル、トリフルオロメチル、（Ｃ_１−Ｃ_４）−アルキル、オキソ、ヒドロキシ、ジフルオロメトキシ、トリフルオロメトキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノおよびジ−（Ｃ_１−Ｃ_４）−アルキルアミノからなる群より独立して選択される１または２個の残基で所望により置換されていてもよく、または
Ｒ^６ＡおよびＲ^６Ｂは、その結合する窒素原子と一緒に結合して、４−ないし７−員のヘテロシクロアルキル環を形成し、その環はＮ、ＯおよびＳから選択される別の環ヘテロ原子を含有してもよく、フルオロ、（Ｃ_１−Ｃ_４）−アルキル、オキソ、ヒドロキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノ、ジ−（Ｃ_１−Ｃ_４）−アルキルアミノおよび（Ｃ_３−Ｃ_６）−シクロアルキルからなる群より独立して選択される１または２個の置換基で所望により置換されていてもよく、
Ｒ^７は（Ｃ_１−Ｃ_６）−アルキル、（Ｃ_３−Ｃ_７）−シクロアルキルおよび４−ないし７−員のヘテロシクロアルキルからなる群より選択され、ここで
（ｉ）該（Ｃ_３−Ｃ_７）−シクロアルキルおよび４−ないし７−員のヘテロシクロアルキルは、フルオロ、ジフルオロメチル、トリフルオロメチル、（Ｃ_１−Ｃ_４）−アルキル、オキソ、ヒドロキシ、ジフルオロメトキシ、トリフルオロメトキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノおよびジ−（Ｃ_１−Ｃ_４）−アルキルアミノからなる群より独立して選択される１または２個の置換基で所望により置換されていてもよく、および
（ｉｉ）該（Ｃ_１−Ｃ_６）−アルキルは、フルオロ、トリフルオロメチル、ヒドロキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノ、ジ−（Ｃ_１−Ｃ_４）−アルキルアミノ、（Ｃ_３−Ｃ_７）−シクロアルキル、フェニル、４−ないし７−員のヘテロシクロアルキルおよび５−または６−員のヘテロアリールからなる群より独立して選択される１、２または３個の置換基で所望により置換されていてもよく、
ここで、該（Ｃ_３−Ｃ_７）−シクロアルキル、フェニル、４−ないし７−員のヘテロシクロアルキルおよび５−または６−員のヘテロアリール置換基は、同様に、フルオロ、クロロ、ブロモ、ジフルオロメチル、トリフルオロメチル、（Ｃ_１−Ｃ_４）−アルキル、オキソ、ヒドロキシ、ジフルオロメトキシ、トリフルオロメトキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノおよびジ−（Ｃ_１−Ｃ_４）−アルキルアミノからなる群より独立して選択される１または２個の残基で所望により置換されていてもよく、
Ｒ^２は水素、フルオロ、クロロまたはメチルであり、
Ｒ^３は水素、メチル、ジフルオロメチル、トリフルオロメチルまたはエチルであり、
Ｒ^４は（Ｃ_１−Ｃ_６）−アルキル、（Ｃ_３−Ｃ_７）−シクロアルキル、フェニルおよび５−または６−員のヘテロアリールからなる群より選択され、ここで
（ｉ）該（Ｃ_３−Ｃ_７）−シクロアルキル、フェニルおよび５−または６−員のヘテロアリールは、フルオロ、クロロ、シアノ、ジフルオロメチル、トリフルオロメチル、（Ｃ_１−Ｃ_４）−アルキル、ヒドロキシ、ジフルオロメトキシ、トリフルオロメトキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノおよびジ−（Ｃ_１−Ｃ_４）−アルキルアミノからなる群より独立して選択される１または２個の置換基で所望により置換されていてもよく、および
（ｉｉ）該（Ｃ_１−Ｃ_６）−アルキルは、３個までのフルオロ原子で、またはトリフルオロメチル、ヒドロキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノ、ジ−（Ｃ_１−Ｃ_４）−アルキルアミノ、（Ｃ_３−Ｃ_７）−シクロアルキル、フェニル、４−ないし７−員のヘテロシクロアルキルおよび５−または６−員のヘテロアリールからなる群より独立して選択される１または２個の置換基で所望により置換されていてもよく、
ここで、該（Ｃ_１−Ｃ_４）−アルコキシ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノおよびジ−（Ｃ_１−Ｃ_４）−アルキルアミノ置換基の該アルキル基は、同様に、３個までのフルオロ原子で、またはトリフルオロメチル、ヒドロキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノ、ジ−（Ｃ_１−Ｃ_４）−アルキルアミノおよび４−ないし７−員のヘテロシクロアルキルから独立して選択される１または２個の残基で所望により置換されていてもよく、および該（Ｃ_３−Ｃ_７）−シクロアルキル、フェニル、４−ないし７−員のヘテロシクロアルキルおよび５−または６−員のヘテロアリール基は、同様に、フルオロ、クロロ、シアノ、ジフルオロメチル、トリフルオロメチル、（Ｃ_１−Ｃ_４）−アルキル、オキソ、ヒドロキシ、ジフルオロメトキシ、トリフルオロメトキシ、（Ｃ_１−Ｃ_４）−アルコキシ、アミノ、モノ−（Ｃ_１−Ｃ_４）−アルキルアミノおよびジ−（Ｃ_１−Ｃ_４）−アルキルアミノからなる群より独立して選択される１または２個の残基で所望により置換されていてもよく、および
Ｒ^５は水素、（Ｃ_１−Ｃ_４）−アルキルまたはシクロプロピルである］
で示される、４−（インダゾール−５−イル）−４,７−ジヒドロイソオキサゾロ［５,４−ｂ］ピリジン誘導体に関する。 In one embodiment, the present invention provides a compound of the general formula (I):

(I)
Wherein R ¹ is selected from the group consisting of hydrogen, chloro, bromo, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl and phenyl, wherein (i) the (C ₃ -C ₇₎ - cycloalkyl and phenyl, fluoro, chloro, bromo, difluoromethyl, _{trifluoromethyl, (C} 1 -C ₄₎ - alkyl, hydroxy, difluoromethoxy, _{trifluoromethoxy, (C} 1 -C ₄ ) -Alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, (C ₃ -C ₆ ) -cycloalkyl and 4- to 6-membered Optionally substituted with one or two substituents independently selected from the group consisting of heterocycloalkyl,
Wherein the (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, mono- (C ₁ -C ₄ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino substituted The alkyl group of the group may likewise be optionally substituted with hydroxy or (C ₁ -C ₄ ) -alkoxy, and (ii) the (C ₁ -C ₆ ) -alkyl is fluoro, trifluoro methyl, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino, di - _(C 1 -C ₄₎ - _alkylamino, (C 3 _-C 7) - Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl. At best,
Wherein the (C ₃ -C ₇ ) -cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl substituents are likewise fluoro, chloro, bromo, difluoro methyl, _{trifluoromethyl, (C} 1 -C ₄₎ - alkyl, oxo, hydroxy, difluoromethoxy, _{trifluoromethoxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkyl Optionally substituted with 1 or 2 residues independently selected from the group consisting of amino and di- (C ₁ -C ₄ ) -alkylamino, or R ¹ is of the formula —NR ^6A R ^6B or —OR ⁷ , wherein R ^6A and R ^6B are hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloal Is selected kill and 4- to 7-membered independently from the group consisting of heterocycloalkyl, wherein (i) the (C 3 _-C 7) _- heterocycloalkyl cycloalkyl and 4- to 7-membered , Fluoro, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, oxo, hydroxy, difluoromethoxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄₎ - alkylamino and di - (C 1 _-C 4) _- may be optionally substituted with 1 or 2 substituents selected independently from the group consisting of alkylamino, and (ii) the _(C 1 -C ₆₎ - alkyl, fluoro, trifluoromethyl, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ) - alkylamino, di - _(C 1 -C ₄₎ - _{alkylamino, (C} 3 -C ₇₎ - cycloalkyl, phenyl, 4-to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of aryl,
Wherein the (C ₃ -C ₇ ) -cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl substituents are likewise fluoro, chloro, bromo, difluoromethyl, _{trifluoromethyl, (C} 1 -C ₄₎ - alkyl, oxo, hydroxy, difluoromethoxy, _{trifluoromethoxy, (C} 1 -C ₄₎ - alkoxy, amino, mono _- (C 1 _-C 4) _- Optionally substituted with one or two residues independently selected from the group consisting of alkylamino and di- (C ₁ -C ₄ ) -alkylamino, or R ^6A and R ^6B are Combined with the nitrogen atom to form a 4- to 7-membered heterocycloalkyl ring, wherein the ring is another selected from N, O and S It may contain a hetero atom, _{fluoro, (C} 1 -C ₄₎ - alkyl, oxo, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino, Optionally substituted with 1 or 2 substituents independently selected from the group consisting of di- (C ₁ -C ₄ ) -alkylamino and (C ₃ -C ₆ ) -cycloalkyl,
R ⁷ is selected from the group consisting of (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl and 4- to 7-membered heterocycloalkyl, wherein (i) the (C ₃ -C ₇₎ - heterocycloalkyl cycloalkyl and 4- to 7-membered, fluoro, difluoromethyl, _{trifluoromethyl, (C} 1 -C ₄₎ - alkyl, oxo, hydroxy, difluoromethoxy, trifluoromethoxy, 1 or 2 independently selected from the group consisting of (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino may be optionally substituted with substituents, and (ii) the _(C 1 -C ₆₎ - alkyl, fluoro, trifluoromethyl, hydroxy, C ₁ -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino, di - _(C 1 -C ₄₎ - _{alkylamino, (C} 3 -C ₇₎ - cycloalkyl, phenyl, Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of 4- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl,
Wherein the (C ₃ -C ₇ ) -cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl substituents are likewise fluoro, chloro, bromo, difluoromethyl, _{trifluoromethyl, (C} 1 -C ₄₎ - alkyl, oxo, hydroxy, difluoromethoxy, _{trifluoromethoxy, (C} 1 -C ₄₎ - alkoxy, amino, mono _- (C 1 _-C 4) _- Optionally substituted with 1 or 2 residues independently selected from the group consisting of alkylamino and di- (C ₁ -C ₄ ) -alkylamino,
R ² is hydrogen, fluoro, chloro or methyl;
R ³ is hydrogen, methyl, difluoromethyl, trifluoromethyl or ethyl;
R ⁴ is selected from the group consisting of (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein (i) the (C ₃ -C ₇ ) -cycloalkyl, phenyl and 5- or 6-membered heteroaryl are fluoro, chloro, cyano, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, hydroxy, difluoromethoxy, Independently selected from the group consisting of trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino that 1 or may be optionally substituted by two substituents, and (ii) the (C 1 _-C 6) _- alkyl, fluoro up to 3 heteroatoms, Trifluoromethyl, _hydroxy, other _(C 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino, di - _(C 1 -C ₄₎ - alkylamino, _{(C 3} - C ₇₎ - cycloalkyl substituted phenyl, optionally with one or two substituents independently selected from the group consisting of heterocycloalkyl and 5- or 6-membered heteroaryl without 4- to 7-membered May have been
Where the alkyl groups of the (C ₁ -C ₄ ) -alkoxy, mono- (C ₁ -C ₄ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino substituents are fluoro atom up to three or trifluoromethyl, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino, di _- (C 1 _-C 4) _- alkylamino and 4 to may be optionally substituted with one or two residues chosen independently from 7-membered heterocycloalkyl, and said (C 3 _-C 7) _- cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl group may likewise fluoro, chloro, cyano, difluoromethyl, trifluoromethyl, (C ₁ C ₄₎ - alkyl, oxo, hydroxy, difluoromethoxy, _{trifluoromethoxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino and di - _(C 1 -C ₄ ) -Alkylamino optionally substituted with 1 or 2 residues independently selected from the group consisting of: and R ⁵ is hydrogen, (C ₁ -C ₄ ) -alkyl or cyclopropyl is there]
And 4- (indazol-5-yl) -4,7-dihydroisoxazolo [5,4-b] pyridine derivatives represented by the formula:

  The compounds of the present invention may also exist in the form of their salts, hydrates and / or solvates.

The target salts of the present invention are preferably pharmaceutically acceptable salts of the compounds of the present invention (eg, SM Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci. 1977, 66, 1-19). checking).

Pharmaceutically acceptable salts are acid addition salts of mineral acids, carboxylic acids and sulfonic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid , Naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid salts.

Pharmaceutically acceptable salts also include, for example, preferably alkali metal salts (eg, sodium and potassium salts), alkaline earth metal salts (eg, calcium and magnesium salts) and ammonia or organic amines, illustratively preferably Ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, N-methylpiperidine, dihydroabiethylamine, arginine, lysine and ethylenediamine Includes salts of conventional bases such as ammonium salts derived from more.

The hydrate of the compound of the present invention or a salt thereof is a stoichiometric composition of the compound and water, such as hemi-, mono- or di-hydrate.

A solvate of the compound of the present invention or a salt thereof is a stoichiometric composition of the compound and the solvent.

  The compounds of the present invention may exist in the form of isomers (enantiomers, diastereomers) due to the properties of the asymmetric center or due to restricted rotation. Any isomer may have an asymmetric center in the (R)-, (S)-or (R, S) -configuration.

  When two or more asymmetric centers are present in the compounds of the present invention, several diastereomers and enantiomers of the exemplified structures are often possible, pure diastereomers and pure enantiomers It will also be understood that represents a preferred example. Pure stereoisomers, pure diastereomers, pure enantiomers and mixtures thereof are intended to be within the scope of the present invention.

  Geometric isomers due to structural properties for double bonds or rings may exist in cis (= Z-) or trans (= E-) forms, both forms of isomers being included within the scope of the present invention. .

  All isomers of the compounds of the present invention, either isolated, pure, partially pure, or racemic mixtures, are included within the scope of the present invention. Purification of the isomer and separation of the isomer mixture can be done by standard methods known in the art. For example, diastereomeric mixtures can be separated into individual isomers by chromatographic methods or crystallization, and racemates can be separated into individual enantiomers by either chromatographic operation or resolution in a chiral phase.

  In addition, all possible tautomeric forms of the above-mentioned compounds are also encompassed by the present invention.

  Unless otherwise stated, the following definitions apply to substituents and residues used throughout the specification and claims:

Alkyl generally represents a straight-chain or branched saturated hydrocarbon group having 1-6 carbon atoms, preferably 1-4, more preferably 1-3. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl. The same applies to groups such as alkoxy, monoalkylamino, dialkylamino and the like.

Alkoxy illustratively preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

Monoalkylamino generally represents an amino group in which one alkyl residue is bonded to a nitrogen atom. Non-limiting examples include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, tert-butylamino.

Dialkylamino generally represents an amino group in which two independently selected alkyl residues are attached to the nitrogen atom. Non-limiting examples include N, N-dimethylamino, N, N-diethylamino, N, N-di-n-propylamino, N, N-diisopropylamino, N-ethyl-N-methylamino, N-methyl-N -N-propylamino, N-isopropyl-N-methylamino, N-isopropyl-Nn-propylamino, Nn-butyl-N-methylamino, N-tert-butyl-N-methylamino .

Cycloalkyl generally represents a mono- or bicyclic saturated hydrocarbon group having 3 to 7, preferably 3 to 6, ring carbon atoms. Monocyclic cycloalkyl groups are preferred. Non-limiting examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1] heptyl.

Heterocycloalkyl is generally 3 to 6, preferably 3 to 5 carbon atoms and up to 2 heteroatoms independently selected from the group consisting of N, O, S, SO and SO ₂ And / or represents a mono- or bicyclic saturated heterocyclic group having a total of 4 to 7, preferably 4 to 6 ring atoms, including a hetero group, the ring system being linked via a ring carbon atom Or, if possible, can be linked via a ring nitrogen atom. Non-limiting examples include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, sulfolanyl, 1,3-dioxolanyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothio Pyranyl, 1,3-dioxanyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl, perhydroazepinyl, perhydro-1,4-diazepinyl, perhydro-1,4- Oxazepinyl, 7-azabicyclo [2.2.1] heptyl, 3-azabicyclo [32.0] heptyl, 7-azabicyclo [41.0] heptyl, 2,5-diazabicyclo [2.2.1] Heptyl, 2-oxa-5-azabicyclo [ .2.1] heptyl. Illustratively preferably having up to two heteroatoms selected from the group consisting of N and O, preferably azetidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, tetrahydropyranyl, 1,4-dioxanyl, piperidinyl 4- to 6-membered monocyclic heterocycloalkyl groups such as, piperazinyl, and morpholinyl are particularly preferred.

Azetidino, pyrrolidino, piperidino, piperazino and morpholino are specifically
An individual heterocycloalkyl group attached to the residue of a molecule through a ring nitrogen atom.

A heteroaryl generally has a total of 5 or 6 ring atoms, including 2 to 5 carbon atoms and up to 3 heteroatoms independently selected from the group consisting of N, O and S. Represents a monocyclic aromatic heterocyclic group, the ring system of which can be attached via a ring carbon atom or, if possible, a ring nitrogen atom. Non-limiting examples include furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl. 6-membered heteroaryl groups having up to 2 nitrogen atoms, such as pyridyl, pyrimidyl, pyridazinyl and pyrazinyl, and N, O and S, such as thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl and isoxazolyl Preference is given to 5-membered heteroaryl groups having up to 2 heteroatoms selected from the group consisting of

Halogen represents fluorine, chlorine, bromine and iodine groups. Fluorine and iodine groups are preferred.

Oxo represents a double-bonded oxygen atom.

  Throughout this application, for simplicity, the use of the singular is preferred over the plural, but is generally intended to include the plural unless specifically stated otherwise. For example, the term “a method of treating a disease in a patient comprising administering an effective amount of a compound of formula (I) to the patient” refers to the simultaneous treatment of a plurality of diseases, as well as a plurality of compounds of formula (I). It is intended to include administration.

In a preferred embodiment, the invention is a compound of general formula (I), wherein R ¹ is hydrogen, (C ₁ -C ₆ ) -alkyl and (C ₃ -C ₆ ) -cycloalkyl. more selected, wherein (i) the _(C 3 -C ₆₎ - cycloalkyl, fluoro, _{trifluoromethyl, (C} 1 -C ₄₎ - alkyl, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, 1 or independently selected from the group consisting of amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino and 4- to 6-membered heterocycloalkyl Optionally substituted with two substituents, and (ii) the (C ₁ -C ₆ ) -alkyl is fluoro, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, a Mino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, (C ₃ -C ₆ ) -cycloalkyl, 4- to 6-membered heterocycloalkyl and Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of 5- or 6-membered heteroaryl,
Wherein the (C ₃ -C ₆ ) -cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- or 6-membered heteroaryl substituents are likewise fluoro, chloro, difluoromethyl, tri _{fluoromethyl, (C} 1 -C ₄₎ - alkyl, oxo, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino and di - _(C 1 -C ₄ ) -Alkylamino may be optionally substituted with 1 or 2 residues independently selected from the group consisting of: or R ¹ is a group of formula —OR ⁷ where R ⁷ is ( C ₁ -C ₆₎ - alkyl and _(C 3 -C ₆₎ - is selected from the group consisting of cycloalkyl, wherein (i) the _(C 3 -C ₆₎ - cycloalkyl, fluoro, trifluoromethyl , _(C 1 -C ₄₎ - alkyl, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino and di - _(C 1 -C ₄₎ - alkylamino Optionally substituted with one or two substituents independently selected from the group consisting of: and (ii) the (C ₁ -C ₆ ) -alkyl is fluoro, trifluoromethyl, hydroxy , _(C 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino, di - _(C 1 -C ₄₎ - _{alkylamino, (C} 3 -C ₆₎ - cycloalkyl and Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of 4- to 6-membered heterocycloalkyl,
Wherein the (C ₃ -C ₆ ) -cycloalkyl and 4- to 6-membered heterocycloalkyl substituents are likewise fluoro, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, oxo, ₁ independently selected from the group consisting of hydroxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino Or optionally substituted with 2 residues,
R ² is hydrogen or fluoro,
R ³ is hydrogen, methyl, difluoromethyl or trifluoromethyl;
R ⁴ is selected from the group consisting of (C ₁ -C ₄ ) -alkyl, cyclopropyl, phenyl and pyridyl, wherein (i) said cyclopropyl is independently from the group consisting of fluoro, trifluoromethyl and methyl Optionally substituted with one or two selected substituents,
(Ii) The phenyl and pyridyl are desired with 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, cyano, difluoromethyl, trifluoromethyl and (C ₁ -C ₄ ) -alkyl. And (iii) the (C ₁ -C ₄ ) -alkyl is up to 3 fluoro atoms or (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C 4) _- alkylamino, di _- (C 1 _-C 4) - optionally 1 or 2 substituents selected alkylamino and 4- to 6-membered independently from the group consisting of heterocycloalkyl May be replaced by
Here, the alkyl group of the (C ₁ -C ₄ ) -alkoxy substituent is likewise up to 3 fluoro atoms, or (C ₁ -C ₄ ) -alkoxy, amino, mono- (C _1- C ₄₎ - alkylamino, di _- (C 1 _-C 4) - optionally alkyl amino and 4- to 6-membered one or two residues independently selected from the group consisting of heterocycloalkyl May be replaced,
Here, the 4- to 6-membered heterocycloalkyl group is, similarly, fluoro, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, oxo, (C ₁ -C ₄ ) -alkoxy, amino, Optionally substituted with 1 or 2 residues independently selected from the group consisting of mono- (C ₁ -C ₄ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino Well, and relates to compounds wherein R ⁵ is hydrogen or methyl.

In another embodiment, the invention relates to compounds of the general formula (I), wherein R ² is hydrogen or fluoro.

In yet another embodiment, the invention relates to compounds of general formula (I), wherein R ³ is hydrogen or methyl.

In another embodiment, the invention relates to compounds of general formula (I), wherein R ⁵ is hydrogen.

In a further preferred embodiment, the present invention is a compound of general formula (I) comprising:
R ¹ is hydrogen or optionally (C ₁ -C ₃ ) -alkoxy, or (C ₁ -C ₄ ) -alkyl optionally substituted with up to 3 fluoro atoms, or R ¹ is of the formula A group of —OR ⁷ , wherein R ⁷ is optionally up to 3 fluoro atoms, or hydroxy, (C ₁ -C ₃ ) -alkoxy, amino, mono- (C ₁ -C ₃ ) -alkylamino , Di- (C ₁ -C ₃ ) -alkylamino, azetidino, pyrrolidino, piperidino, piperazino and morpholino optionally substituted (C ₁ -C ₄ ) -alkyl. ,
Wherein the azetidino, pyrrolidino, piperidino, piperazino and morpholino groups are likewise optionally substituted with 1 or 2 residues independently selected from the group consisting of fluoro, methyl, oxo, methoxy and ethoxy You may,
R ² is hydrogen or fluoro,
R ³ is hydrogen or methyl;
R ⁴ is selected from the group consisting of (C ₁ -C ₄ ) -alkyl, phenyl and pyridyl, wherein
(I) The (C ₁ -C ₄ ) -alkyl is optionally up to 3 fluoro atoms or (C ₁ -C ₃ ) -alkoxy, amino, mono- (C ₁ -C ₃ ) -alkyl Optionally substituted with one substituent selected from the group consisting of amino and di- (C ₁ -C ₃ ) -alkylamino, and (ii) the phenyl and pyridyl are fluoro, chloro, cyano, It relates to compounds, optionally substituted with 1 or 2 substituents independently selected from the group consisting of methyl and trifluoromethyl, and wherein R ⁵ is hydrogen.

In a particularly preferred embodiment, the present invention relates to a compound represented by the general formula (I),
R ¹ is hydrogen or (C ₁ -C ₄ ) -alkyl, or R ¹ is a group of formula —OR ⁷ , where R ⁷ is (C ₁ -C ₄ ) -alkyl;
R ² is hydrogen or fluoro,
R ³ is hydrogen or methyl;
R ⁴ is (C ₁ -C ₄ ) -alkyl optionally substituted with up to 3 fluoro atoms;
Relates to compounds wherein R ⁵ is hydrogen.

  Residue definitions specifically indicated in individual combinations or preferred combinations of residues may also be replaced with other residue definitions as desired, regardless of the particular combination shown for that residue. . A combination of two or more of the above preferred ranges is particularly preferred.

（ＩＩ）
［式中、Ｒ^１およびＲ^２は上記と同意義である］
で示されるアルデヒドを、式（ＩＩＩ）：

（ＩＩＩ）
［式中、Ｒ^４は上記と同意義である］
で示されるシアノケトンまたはそのナトリウムエノラートと、酸、酸／塩基の組み合わせ、および／または脱水剤の存在下で反応させ、式（ＩＶ）：

（ＩＶ）
［式中、Ｒ^１、Ｒ^２およびＲ^４は上記と同意義である］
で示される化合物を得、ついで該化合物を式（Ｖ）：

（Ｖ）
［式中、Ｒ^３は上記と同意義である］
で示される化合物と、所望により酸触媒の助けを借りて、縮合させ、式（Ｉ−Ａ）：

（Ｉ−Ａ）
［式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は上記と同意義である］
で示される化合物を得、
所望により、必要とあれば、つづいて（ｉ）化合物（Ｉ−Ａ）をその対応する個々のエナンチオマーおよび／またはジアステレオマーに好ましくはクロマトグラフィー法を用いて分離し、および／または（ｉｉ）化合物（Ｉ−Ａ）を、溶媒および／または酸または塩基で処置することにより、その対応する個々の水和物、溶媒和物、塩および／またはその塩の水和物または溶媒和物に変換する、方法に関する。 In another embodiment, the present invention provides a process for preparing a compound of general formula (I), wherein R ⁵ is hydrogen, first comprising formula (II):

(II)
[Wherein R ¹ and R ² are as defined above]
An aldehyde represented by formula (III):

(III)
[Wherein R ⁴ is as defined above]
In the presence of an acid, an acid / base combination, and / or a dehydrating agent, and a compound of formula (IV):

(IV)
[Wherein R ¹ , R ² and R ⁴ are as defined above]
The compound represented by formula (V):

(V)
[Wherein R ³ is as defined above]
With a compound of formula (IA), optionally with the aid of an acid catalyst,

(IA)
[Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above]
To obtain a compound represented by
If desired, if necessary, subsequently (i) separating compound (IA) into its corresponding individual enantiomers and / or diastereomers, preferably using chromatographic methods, and / or (ii) Compound (IA) is converted to its corresponding individual hydrate, solvate, salt and / or hydrate or solvate of the salt by treatment with solvent and / or acid or base How to do.

  Steps (II) + (III) → (IV) and (IV) + (V) → (IA) are generally carried out in the temperature range from + 20 ° C. to the boiling point of the solvent, under an external pressure, under an inert solvent Implemented in.

  Suitable solvents for this purpose are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, hydrocarbons such as hexane, cyclohexane, benzene, toluene or xylene, dichloromethane, trichloromethane, tetra Halohydrocarbons such as chloromethane, trichloroethane, 1,2-dichloroethane, chlorobenzene or chlorotoluene, ethers such as tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, or other solvents such as acetonitrile, pyridine or acetic acid It is.

  It is equally possible to use mixtures of these solvents. The reaction of (II) + (III) → (IV) is preferably carried out in dichloromethane, toluene, ethanol or isopropanol at the respective reflux temperature and at ambient pressure, and (IV) + (V) → ( The reaction of IA) is preferably carried out in ethanol or isopropanol at reflux temperature and also under ambient pressure.

  The reaction (II) + (III) → (IV) can advantageously be carried out in the presence of an acid, an acid / base combination and / or a dehydrating agent such as, for example, molecular sieves. Examples of suitable acids are acetic acid, trifluoroacetic acid, methanesulfonic acid and p-toluenesulfonic acid; suitable bases are in particular piperidine or pyridine. Depending on the reactivity of the components, the conversion of (IV) + (V) → (IA) can be carried out without further aids and can be accelerated using an acid catalyst, preferably acetic acid. Can be done.

  The reaction route of (II) → (IV) → (IA) is the above-described two separate steps or by using a one-pot operation, that is, isolation of an intermediate of compound (IV). [Synthesis of 1,4-dihydropyridine is generally described in, for example, DM Stout, AI Meyers, Chem. Rev. 1982, 82, 223-243; H. Meier et al., Liebigs Ann. Chem. 1977, 1888; see H. Meier et al., Supra, 1977, 1895; H. Meier et al., Supra, 1976, 1762; F. Bossert et al., Angew. Chem. 1981, 93, 755].

（ＶＩ）
［式中、Ｒ^１、Ｒ^２、Ｒ^３およびＲ^４は上記と同意義であり、ＰＧはｔｅｒｔ−ブトキシカルボニル、２−（トリメチルシリル）エトキシメチルまたはｐ−メトキシベンジルなどの適当なインダゾール保護基を表す］
で示されるインダゾールＮ^１−保護誘導体に変換し、
つづいて、ジヒドロピリジンを、塩基の存在下で、式（ＶＩＩ）：

［式中、
Ｒ^５Ａは（Ｃ_１−Ｃ_４）−アルキルまたはシクロプロピルであり、
Ｚはハロゲン、メシラート、トリフラートまたはトシラートなどの脱離基である］
で示される化合物を用いてＮ−アルキル化に付して式（ＶＩＩＩ）：

（ＶＩＩＩ）
［式中、ＰＧ、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５Ａは上記と同意義である］
で示される化合物を得、その後で保護基ＰＧを標準的操作を用いて除去し、式（Ｉ−Ｂ）：

（Ｉ−Ｂ）
［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４およびＲ^５Ａは上記と同意義である］
で示される化合物を得ることで調製され得る。 A compound of formula (I) wherein R ⁵ is (C ₁ -C ₄ ) -alkyl or cyclopropyl is obtained by _first converting a compound of formula (IA) by standard methods,

(VI)
Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above, and PG is a suitable indazole protecting group such as tert-butoxycarbonyl, 2- (trimethylsilyl) ethoxymethyl or p-methoxybenzyl. To express]
Indazole N ¹ -protected derivative represented by
Subsequently, dihydropyridine in the presence of a base has the formula (VII):

[Where:
R ^5A is (C ₁ -C ₄ ) -alkyl or cyclopropyl;
Z is a leaving group such as halogen, mesylate, triflate or tosylate]
N-alkylation using a compound of formula (VIII):

(VIII)
[Wherein, PG, R ¹ , R ² , R ³ , R ⁴ and R ^5A are as defined above]
After which the protecting group PG is removed using standard procedures to obtain a compound of formula (IB):

(IB)
[Wherein R ¹ , R ² , R ³ , R ⁴ and R ^5A are as defined above]
Can be prepared by obtaining a compound represented by

  The introduction and removal of the indazole protecting group PG in steps (IA) → (VI) and (VIII) → (IB) is generally carried out by standard methods well known in the art. [See, e.g., TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Wiley, New York, 1999; M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, Berlin, 1984] . It is preferable that tert-butoxycarbonyl (Boc), 2- (trimethylsilyl) ethoxymethyl (SEM) or p-methoxybenzyl (PMB) is used as a protecting group in the above-described steps. Removal of these groups is generally carried out by reaction with a strong acid such as hydrogen chloride, hydrogen bromide or trifluoroacetic acid in an inert solvent such as water, dioxane, dichloromethane or acetic acid; required Depending on the, the removal can also be carried out without the use of an additional inert solvent. When using SEM groups for indazole protection, cleavage is also accomplished separately by treatment with a fluoride source such as potassium fluoride or tetrabutylammonium fluoride in an inert solvent such as tetrahydrofuran.

However, in some cases it may be more possible to perform the dihydropyridine N-alkylation step without prior indazole N ¹ -nitrogen blockade, preferably to separate the resulting product mixture using chromatographic operations. convenient.

  Inert solvents for the alkylation reaction (VI) + (VII) → (VIII) are for example ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxyethane, Hydrocarbons such as benzene, toluene, xylene, hexane or cyclohexane, halohydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, chlorobenzene or chlorotoluene, or acetonitrile, N, N -Other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP) or pyridine. It is also possible to use a mixture of these solvents. Preference is also given to using dichloromethane, tetrahydrofuran, dimethylformamide or mixtures thereof.

  Suitable bases for step (VI) + (VII) → (VIII) are in particular alkali metal or alkaline earth metal carbonates such as lithium carbonate, sodium, calcium or cesium, alkali metal hydrides such as sodium or potassium hydride. Sterically shielded alkali alkoxides such as sodium or potassium tert-butoxide, sterically shielded alkali amides such as lithium, sodium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide or triethylamine, N-methylmorpholine, Organic amines such as N-methylpiperidine, N, N-diisopropylethylamine or pyridine. Potassium carbonate, cesium carbonate, sodium hydride or triethylamine are preferably used.

  Reaction (VI) + (VII) → (VIII) is generally carried out at ambient temperature in the temperature range of −20 ° C. to + 120 ° C., preferably 0 ° C. to + 80 ° C.

If appropriate, start with other compounds of the formula (I) according to the invention obtained according to the process described above and modify the individual substituents, in particular the functional groups of the substituents listed under R ¹ and R ⁴ Thus, further compounds of formula (I) can also be prepared. These variations are conventional methods known to those skilled in the art, such as nucleophilic or electrophilic substitution reactions, transition metal mediated coupling reactions (eg Suzuki and Heck reactions), oxidation, reduction, hydrogenation, halogenation, alkyl Also included are reactions such as hydration, amination, hydroxylation and etherification, and the introduction and removal of temporary protecting groups.

  Compounds of formula (II) are described in the literature or can be prepared from readily available starting materials by applying standard methods described in the literature [see, eg, G. Luo et al., J. Org. Chem. 71, 5392 (2006), and the operations described in WO 2007 / 124288-A1, WO 2005 / 056550-A2, US 2005 / 0227968-A1 and EP 1510516-A1].

（ＩＩ−Ａ）
［式中、Ｒ^２は上記と同意義である］
で示される親のインダゾリルアルデヒドを、第一に、標準的操作を用いて、３位でハロゲン化し、式（ＩＸ）：

（ＩＸ）
［式中、
ＰＧおよびＲ^２は上記と同意義であり、
Ｘはクロロ、ブロモまたはヨードであり、
Ｒ^８は（Ｃ_１−Ｃ_４）−アルキルを表すか、または両方のＲ^８残基が一緒になって−（ＣＨ_２）_２−または−（ＣＨ_２）_３−架橋を形成する］
で示されるジ保護誘導体に変形し、第二に、式（ＩＸ）の化合物を、適当な遷移金属触媒、好ましくは銅またはパラジウム触媒を用いて、
［Ａ］式（Ｘ）：

［式中、
Ｒ^１Ａは、上記した式−ＮＲ^６ＡＲ^６Ｂまたは−ＯＲ^７の各々のＮ−またはＯ−連結Ｒ^１残基を表す］
で示される化合物とカップリングさせて、式（ＸＩ−Ａ）

（ＸＩ−Ａ）
［式中、ＰＧ、Ｒ^１Ａ、Ｒ^２およびＲ^８は上記と同意義である］
で示される化合物を得るか、または
［Ｂ］式（ＸＩＩ）：

［式中、
Ｒ^１Ｂは、上記したように、（Ｃ_１−Ｃ_６）−アルキル、（Ｃ_３−Ｃ_７）−シクロアルキルおよびフェニルからなる群より選択される所望により置換されていてもよいＣ−連結Ｒ^１残基を表し、および
Ｑは−Ｂ（ＯＲ^９）_２、−ＭｇＨａｌ、−ＺｎＨａｌまたは−Ｓｎ（Ｒ^１０）_３基を表し、ここで、
Ｈａｌはハロゲン、特にクロロ、ブロモまたはヨードであり、
Ｒ^９は水素または（Ｃ_１−Ｃ_４）−アルキルであるか、または両方のＲ^９残基が一緒になって−（ＣＨ_２）_２−、−Ｃ（ＣＨ_３）_２−Ｃ（ＣＨ_３）_２−、−（ＣＨ_２）_３−または−ＣＨ_２−Ｃ（ＣＨ_３）_２−ＣＨ_２−架橋であり、
Ｒ^１０は（Ｃ_１−Ｃ_４）−アルキルである］
で示される化合物とカップリングさせて、式（ＸＩ−Ｂ）：

（ＸＩ−Ｂ）
［式中、ＰＧ、Ｒ^１Ｂ、Ｒ^２およびＲ^８は上記と同意義である］
で示される化合物を得、
最終的に、標準的方法を用いて保護基をその後でまたは同時に除去し、各々、式（ＩＩ−Ｂ）および（ＩＩ−Ｃ）：

［式中、Ｒ^１Ａ、Ｒ^１ＢおよびＲ^２は上記と同意義である］
で示される３−置換インダゾリルアルデヒドを得る。 In one synthetic route, formula (II-A):

(II-A)
[Wherein R ² is as defined above]
The parent indazolylaldehyde represented by is first halogenated at the 3-position using standard procedures to obtain a compound of formula (IX):

(IX)
[Where:
PG and R ² are as defined above,
X is chloro, bromo or iodo;
R ⁸ represents (C ₁ -C ₄ ) -alkyl or both R ⁸ residues together form a — (CH ₂ ) ₂ — or — (CH ₂ ) ₃ — bridge]
And secondly the compound of formula (IX) is converted using a suitable transition metal catalyst, preferably a copper or palladium catalyst,
[A] Formula (X):

[Where:
R ^1A represents each N- or O-linked R ¹ residue of the formula —NR ^6A R ^6B or —OR ⁷ as described above]
Coupled with a compound of formula (XI-A)

(XI-A)
[Wherein, PG, R ^1A , R ² and R ⁸ are as defined above]
Or [B] Formula (XII):

[Where:
R ^1B is an optionally substituted C-linked R selected from the group consisting of (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl and phenyl as described above. Represents ^one residue, and Q represents a —B (OR ⁹ ) ₂ , —MgHal, —ZnHal or —Sn (R ¹⁰ ) ₃ group, where
Hal is halogen, in particular chloro, bromo or iodo,
R ⁹ is hydrogen or (C ₁ -C ₄ ) -alkyl, or both R ⁹ residues taken together —— (CH ₂ ) ₂ —, —C (CH ₃ ) ₂ —C (CH ₃ ) ₂₋ , — (CH ₂ ) ₃ — or —CH ₂ —C (CH ₃ ) ₂ —CH ₂ —
R ¹⁰ is (C ₁ -C ₄ ) -alkyl]
Coupled with a compound of formula (XI-B):

(XI-B)
[Wherein, PG, R ^1B , R ² and R ⁸ are as defined above]
To obtain a compound represented by
Finally, the protecting groups are subsequently or simultaneously removed using standard methods to give formulas (II-B) and (II-C):

[Wherein R ^1A , R ^1B and R ² are as defined above]
To give a 3-substituted indazolylaldehyde.

Inert solvents suitable for steps (IX) + (X) → (XI-A) and (IX) + (XII) → (XI-B) are, for example, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl Ethers, ethers such as diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and bis- (2-methoxyethyl) -ether, or acetonitrile, dimethyl sulfoxide (DMSO), N, Includes dipolar aprotic solvents such as N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), N, N′-dimethylpropyleneurea (DMPU) and pyridine . When an aliphatic alcohol [R ^1A is OR ⁷ and R ⁷ is alkyl] is used as the coupling reagent (X), the excess may also be provided as a solvent. The use of a mixture of these solvents is also feasible. Preferred solvents are toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and mixtures thereof.

  The coupling reactions (IX) + (X) → (XI-A) and (IX) + (XII) → (XI-B) are carried out with the aid of a transition metal catalyst. For this purpose, in particular copper catalysts such as copper (I) iodide, palladium on activated carbon, palladium (II) acetate, bis (dibenzylideneacetone) -palladium (0), tris (dibenzylideneacetone) -dipalladium ( 0), tetrakis (triphenylphosphine) -palladium (0), bis (triphenylphosphine) -palladium (II) chloride, bis (acetonitrile) -palladium (II) chloride or [1,1′-bis (diphenylphosphino) ) Ferrocene] -palladium (II) chloride, such as, for example, dicyclohexyl [2 ′, 4 ′, 6′-tris (1-methylethyl) biphenyl-2-yl] phosphane (XPHOS) or 4, 5-bis (diphenylphosphino) -9,9-dimethylxanthene (Xant phos) and other additional phosphane ligands are suitable [eg, J. Hassan et al., Chem. Rev. 102, 1359-1469 (2002); V. Farina, V. Krishnamurthy and WJ Scott: See The Stille Reaction, Wiley, New York, 1998].

  Steps (IX) + (X) → (XI-A) and (IX) + (XII) → (XI-B) are usually performed at a temperature range of + 20 ° C. to + 200 ° C., preferably + 80 ° C. to + 180 ° C. Performed at ambient pressure. However, it is also possible to carry out these reactions at high pressure or low pressure (for example in the range of 0.5 to 5 bar). Furthermore, the deformation can advantageously be made by irradiating with microwaves simultaneously.

Alternatively, such an indazole coupling reaction is carried out later in the preparation process using, for example, a compound of formula (IA) or (IB) as a precursor, where R ¹ is chloro or bromo. May be. The reaction parameters described above for the transformations (IX) + (X) → (XI-A) and (IX) + (XII) → (XI-B) such as solvents and catalysts apply analogously. In some cases, depending on the particular reaction conditions and reagents, these coupling reactions are directly, i.e., indazole N ¹ previously - without protecting the nitrogen can be performed.

  Compounds of formula (II-A), (III), (V), (VII), (X) and (XII) are either commercially available, described in the literature, or standard methods described in the literature. It can be made from available starting materials by application.

  The preparation of the compounds of the present invention can be illustrated by the following synthetic route. More detailed operations are described in the experimental section describing the examples below.

［ａ）：ＮＣＳ（Ｘ＝Ｃｌ）またはＮＢＳ（Ｘ＝Ｂｒ）またはＩ_２／水性ＮａＯＨ（Ｘ＝Ｉ）；ｂ）：Ｍｅ_３ＳｉＣＨ_２ＣＨ_２ＯＣＨ_２Ｃｌ、Ｃｓ_２ＣＯ_３；ｃ）：ＨＯＣＨ_２ＣＨ_２ＯＨ、触媒ｐ−ＴｓＯＨ；ｄ）：Ｒ^７−ＯＨ、Ｃｓ_２ＣＯ_３、触媒ＣｕＩ；ｅ）：１.ＴＢＡＦ、２.水性ＨＣｌ］

[A): NCS (X = Cl) or NBS (X = Br) or I ₂ / aqueous NaOH (X = I); b): Me ₃ SiCH ₂ CH ₂ OCH ₂ Cl, Cs ₂ CO ₃ ; c): HOCH ₂ CH ₂ OH, catalytic ^{p-TsOH; d): R} 7 -OH, Cs 2 CO 3, catalytic CuI; e):. 1.TBAF, 2 aqueous HCl]

Methods of Use The compounds of the present invention may be used to inhibit the activity or expression of receptor tyrosine kinases, particularly c-Met receptor tyrosine kinases. Accordingly, the compounds of formula (I) are considered valuable as therapeutic agents. Thus, in another embodiment, the present invention relates to a method for treating a disorder related to or mediated by c-Met kinase activity, wherein said treatment is effective in said patient in need thereof. A method is provided comprising administering an amount of a compound of formula (I) as described above. In certain embodiments, the disorder related to c-Met kinase activity is a cell proliferative disorder, particularly cancer.

  The term “treat” or “treatment” as used throughout the specification conventionally refers to managing a subject for the purpose of eradicating, ameliorating, reducing, alleviating, ameliorating, for example, a disease or disorder such as cancer. Used to care.

  The term “subject” or “patient” refers to an organism that may suffer from a cell proliferative disorder, such as humans and non-human animals, or an organism that would otherwise benefit from administering a compound of the invention. Is included. Preferred humans include human patients suffering from a cell proliferative disorder or a condition associated therewith described herein, or human patients prone to suffer from such disorders and the like. The term “non-human animal” refers to non-vertebrates, eg, non-human primates, sheep, cows, dogs, cats and rodents, eg, mammals such as mice, and non-mammals such as birds, amphibians, and reptiles. Including vertebrates.

  The term “disorders associated with or mediated by c-Met” refers to diseases associated with or associated with c-Met activity, such as hyperactivity of c-Met and pathologies associated with these diseases. Include. Examples of “disorders related to or mediated by c-Met” include disorders caused by excessive stimulation of c-Met by abnormally high amounts of c-Met or mutations in c-Met, or abnormally Examples include disorders caused by abnormally high amounts of c-Met activity or c-Met mutations due to high amounts of c-Met.

  The term “c-Met overactivity” refers to c-Met expression in cells that do not normally express c-Met, or active or improved c-Met expression or c -Refers to any of the c-Met activity by cells that do not normally have mutations leading to constitutive activation of Met.

  The term “cell proliferative disorder” encompasses disorders involving undesired or uncontrolled cell growth. The compounds of the present invention can be used to prevent, inhibit, block, reduce, reduce, control, etc., cell proliferation and / or cell division and / or cause apoptosis. This method involves treating a subject in need thereof, including mammals including humans, with a certain amount of a compound of the present invention or a pharmaceutically acceptable salt, isomer thereof, which is effective for treating or preventing the disorders described above. Administration of a body, polymorph, metabolite or solvate.

  In the context of the present invention, cell proliferative or hyperproliferative disorders include, but are not limited to, for example, psoriasis, hyperplasia such as keloids that affect the skin, endometriosis, bone disorders, angiogenesis Or vascular proliferative disorder, pulmonary hypertension, fibrosis, mesangial cell proliferative disorder, colon polyps, polycystic kidney disease, benign prostatic hyperplasia (BPH), and breast, airways, brain, genitals, digestive tract, urinary tract, Includes solid tumors such as cancer of the eye, liver, skin, head and neck, thyroid, parathyroid, and distant metastases of the solid tumors. The disorders also include lymphoma, sarcoma and leukemia.

  Examples of breast cancer include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, non-invasive ductal carcinoma and lobular carcinoma in situ

  Examples of airway cancers include, but are not limited to, small cell and non-small cell lung cancer, and bronchial adenoma and pleuropulmonary blastoma.

  Examples of brain cancer include, but are not limited to, brainstem and hypothalamic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependyma and extraneuropulmonary lobular and pineal tumors To do.

  Male genital tumors include, but are not limited to, prostate and testicular cancer. Tumors of female genital organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, ovarian cancer, vaginal and vulvar cancer, and uterine sarcoma.

  Gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer.

Tumors of the urinary tract include, but are not limited to, bladder cancer, penile cancer, pancreatic cancer, renal pelvic cancer, ureteral cancer, urethral cancer, hereditary and diffuse papillary renal cell carcinoma.
Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.

  Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic cholangiocarcinoma) and mixed hepatocellularity Bile duct cancer is mentioned.

  Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

  Head and neck cancers include, but are not limited to pharyngeal, hypopharyngeal, nasopharyngeal or oropharyngeal cancer, lip and oral cancer, and squamous cell carcinoma.

  Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease and central nervous system lymphoma.

  Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

  Leukemia includes, but is not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia and hairy cell leukemia.

  Fibroproliferative disorders that can be treated with the compounds and methods of the present invention, ie, abnormal formation of extracellular matrix, including pulmonary fibrosis, atherosclerosis, restenosis, cirrhosis, and glomerulonephritis, diabetes Mesangial cell proliferative disorders, including renal disease, including nephropathy, malignant nephrosclerosis, thrombotic microvascular syndrome, graft rejection and glomerulopathy.

  Other pathologies in humans or other mammals that can be treated by administering the compounds of the present invention include diabetic retinopathy, ischemic retinal vein occlusion, retinopathy of prematurity and age-related macular degeneration, joints Includes rheumatic, psoriasis, and bullous disorders associated with subepidermal blistering, including bullous pemphigoid, erythema multiforme and herpes zoster.

  The compounds of the present invention may also be used to prevent and treat airway and lung diseases, gastrointestinal diseases, and bladder and bile duct diseases.

  Although the disorders described above are well characterized in humans, there are similar etiologies in other animals, including mammals, and can be treated by administering the pharmaceutical composition of the present invention.

  The compound of formula (I) may be administered as a single therapeutic agent or in combination with one or more additional therapeutic agents that do not cause unacceptable side effects. This combination therapy comprises administering as a single therapeutic dosage formulation containing a compound of formula (I) and one or more additional therapeutic agents, as well as each of the compounds of formula (I) Of the therapeutic agent itself in separate therapeutic dosage formulations. For example, the compound of formula (I) and the therapeutic agent may be administered to the patient together as a tablet or capsule in a single oral dosage composition, or each agent may be administered in a separate dosage formulation. Good.

  When separate dosage formulations are used, the compound of formula (I) and the one or more additional therapeutic agents are essentially simultaneously (eg, simultaneously) or separately at different times (eg, sequentially). Manually).

  In particular, the compounds of the present invention include other antitumor agents such as alkylating agents, antimetabolites, plant-derived antitumor agents, hormone therapeutic agents, topoisomerase inhibitors, camptothecin derivatives, kinase inhibitors, target drugs, It may be used in combination with antibodies, interferons and / or biological response modifiers, anti-angiogenic compounds, and other anti-tumor drugs, either fixedly or independently. In this regard, the following description is a list of second agents that may be used in combination with the compounds of the present invention, which is illustrative and not limiting:

Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, thiotepa, ranimustine, nimustine, temodromide, altretamine, apadiquan, brostalysin, bendamustine, carmustine, estramustine, Including, hotemustine, glufosfamide, mafosfamide, bendamustine, and mitactol; platinum-coordinated alkylating compounds include, but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin and satraplatin;

Antibody rewards include, but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil alone or in combination with leucovorin, tegafur, doxyfluridine, camphor, cytarabine, cytarabine ocphosphate, enocytabine, Gemcitabine, fludarabine, 5-azacytazine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethiniricytidine, cytosine arabinoside, hydroxyurea, melphalan, nelarabine, noratrexide, ocphosphito, pemetrexed tritrexitole trexole Including trimethrexate, vidarabine, vincristine, and vinorelbine;

Hormonal therapeutic agents include, but are not limited to, exemestane, lupron, anastrozole, doxel calciferol, fadrozole, formestane, 11-beta hydroxysteroid dehydrogenase 1 inhibitor, 17-alpha hydroxylase / 17 , 20 lyase inhibitors such as abiraterone acetate, 5-alpha reductases such as phenasteride and epilisteride, antiestrogens such as tamoxifen and fulvestrant citrate, tolerster, toremifene, raloxifene, lasofoxifene, letrozole, anti-androgens such as bicalutamide , Flutamide, mifepristone, nilutamide, casodex and anti-progesterone, and combinations thereof;

Plant-derived antitumor agents include, for example, substances selected from mitotic inhibitors, epothilones such as sagopilone, ixabepilone and epothilone B, vinblastine, vinflunine, docetaxel and paclitaxel;

Cytotoxic topoisomerase inhibitors include, but are not limited to, aclarubicin, doxorubicin, amonafide, belothecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, difurometecan, irinotecan, topotecan, edotecarin, epeticin, etoposide, exatecan , Dimatecan, lutrotecan, mitoxantrone, pyrambinine, pixanthrone, rubitecan, sobuzoxane, tafluposide and combinations thereof;

Immunological agents include interferons such as interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, and interferon gamma-n1, and other immune enhancing agents such as L19-IL2 and other IL2 derivative, filgrastin, lentinan, schizophyllan, terrasis (TheraCys), ubenimex, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, deniliukin, gemtuzumab, ozogamicin, ibritumomab, imiquimodo, lenoclastoma vaccine , Morglamostim, sargramostim, tasonermine, techleukin, timaracin, tositumomab, biml Encompasses emissions, epratuzumab, Mitsumomabu, oregovomab, pemtumomab, and Purobenge;

A biological response modifier is an agent that modifies a biological defense mechanism or biological response, such as tissue cell survival, proliferation or differentiation, and directs the tissue cell to have anti-tumor activity; Include, for example, krestin, lentinan, schizophyllan, picibanil, promon and ubenimex;

Anti-angiogenic compounds include, but are not limited to, acitretin, aflibercept, angiostatin, apridin, acental, axitinib, recentin, belacizumab, brivanib alanate, silentide, combretastatin, DAST, endostatin, fenretinide, Including halofuginone, pazopanib, ranibizumab, levimastat, remobab, lebrimid, sorafenib, batalanib, squalamine, sunitinib, terratinib, thalidomide, ukulein, and vitaxin;

Antibodies include, but are not limited to, trastuzumab, cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab, lumiliximab, katumaxomab, atachicept, oregovoumab and alemtuzumab.
VEGF inhibitors such as, for example, sorafenib, DAST, bevacizumab, sunitinib, resentin, axitinib, aflibercept, terratinib, brivanib alanate, betalanib, pazopanib, and ranibizumab;

HGFR (HER1) inhibitors such as, for example, cetuximab, panitumumab, vetivix, gefitinib, erlotinib, and zactima;
HER2 inhibitors such as, for example, lapatinib, tratuzumab, and pertuzumab;
MTOR inhibitors such as, for example, temsirolimus, sirolimus / rapamycin, and everolimus;
c-Met inhibitors;
PI3K and AKT inhibitors;
CDK inhibitors such as roscovitine and flavopiridol;

Spindle assembly checkpoint inhibitors and targeted mitotic inhibitors such as PLK inhibitors, Aurora inhibitors (eg, hesperazine), checkpoint kinase inhibitors, and KSP inhibitors such as panobinostat, vorinostat, MS275, verinostat, And HDAC inhibitors such as LBH589;
HSP90 and HSP70 inhibitors;
Proteasome inhibitors such as bortezomib and carfilzomib;
Serf / threonine kinase inhibitors including MEK inhibitors and Raf inhibitors such as sorafenib;
For example, a fernesyltransferase inhibitor such as tipirarunib;

For example, dasatinib, nilotibib, DAST, bosutinib, sorafenib, bevacizumab, sunitinib, AZD2171, axitinib, aflibercept, teratinib, imatinib mesylate, brivanib alanate, pazopanib, patuxib Tyrosine kinase inhibitors, including lapatinib, tratuzumab, pertuzumab, and c-kit inhibitors;

A vitamin D receptor agonist;
Bcl-2 protein inhibitors such as obatoclax, obrimersen sodium, and gossypol;
For example, a cluster of 20 differentiated receptor antagonists such as rituximab;
For example, a ribonucleotide reductase inhibitor such as gemcitabine;
Tumor necrosis apoptosis, including, for example, a ligand receptor 1 agonist such as mapatumumab;

5-hydroxytryptamine receptor antagonists such as, for example, rEV598, xaliprodo, palonosetron hydrochloride, granisetron, zindol, and AB-1001;
Integrin inhibitors, including for example alpha 5-beta1 integrin inhibitors such as E7820, JSM6425, boroximab and endostatin;

Androgen receptor antagonists including, for example, nandrolone decanoate, fluoxymesterone, android, prostaid, andromustine, bicalutamide, flutamide, apocyproterone, apoflutamide, chlormadinone acetate, androcle, tabi, cyproterone acetate, and nilutamide;
Aromatase inhibitors such as, for example, anastrozole, letrozole, test lactone, exemestane, aminoglutethimide, and formestane;
Matrix metalloproteinase inhibitors;

For example, alitretinoin, ampligen, atrasentanbexarotene, bortezomib, bosentan, calcitriol, exrind, hotemstin, ibandronic acid, miltefosine, mitoxantrone, I-asparaginase, procarbazine, decarbazine, hydroxycarbamide, pegaspargase, pent Other anti-cancer agents including statins, tazarotene, velcade, gallium nitrate, camphosphamide, darinaparcin, and tretinoin.

  In preferred embodiments, the compounds of the invention are chemotherapeutic agents (ie, cytotoxic agents), anti-hormonal agents and / or other kinase inhibitors (eg, EGFR inhibitors), mTOR inhibitors and angiogenesis inhibitors, etc. May be used in combination with other targeted therapeutic agents.

  The compounds of the present invention may also be used in cancer treatment in combination with radiation therapy and / or surgical intervention.

  Furthermore, the compound of the formula (I) may be used in its own or in the composition, in research or diagnosis, or as an analytical specimen, etc., well known in the art.

Pharmaceutical Compositions and Methods of Treatment In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described above together with a pharmaceutically acceptable carrier.

  In yet another aspect, the present invention provides a method of making a pharmaceutical composition. The method comprises the step of combining at least one compound of formula (I) as described above with at least one pharmaceutically acceptable carrier and making the resulting combination a suitable dosage form.

  The active ingredient of formula (I) can act systemically and / or locally. For this purpose, the component is administered in a suitable manner, for example oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, trans It can be applied cutaneous, conjunctival, transocularly, or as an implant or stent.

For these application routes, the active ingredient of formula (I) may be administered in a suitable application form.
Useful oral application forms release the active ingredient immediately and / or in modified form, for example tablets (uncoated tablets and coated tablets with eg enteric coatings), capsules, dragees, granules, pellets Application forms such as powders, emulsions, suspensions, solutions and aerosols.

  Parenteral application avoids absorption steps (intravenous, intraarterial, intracardiac, intrathecal or spinal) or absorption steps (intramuscular, subcutaneous, intradermal, percutaneous or intraperitoneal) Can be implemented. Useful parenteral application forms include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilized preparations and sterile powders.

  Suitable forms for other application routes are, for example, inhalation dosage forms (including powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets to be administered lingually, sublingually or buccally or Includes capsules, suppositories, otic and ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, emulsions, pastes, spray powders, implants or stents .

  In a preferred embodiment, a pharmaceutical composition comprising a compound of formula (I) as described above is provided in a form suitable for oral administration. In another preferred embodiment, a pharmaceutical composition comprising a compound of formula (I) as described above is provided in a form suitable for intravenous administration.

  The active ingredients of the formula (I) can be converted into the application forms listed in a manner known per se. This is done using inert non-toxic pharmaceutically suitable excipients. This includes, inter alia, carriers (eg microcrystalline cellulose), solvents (eg liquid polyethylene glycol), emulsifiers (eg sodium dodecyl sulfate), dispersants (eg polyvinyl pyrrolidone), synthetic and natural biopolymers (eg Albumin), stabilizers (eg antioxidants such as ascorbic acid), colorants (eg inorganic pigments such as iron oxide) or taste and / or flavoring agents.

  In another embodiment, the present invention is a method of treating a cell proliferative disorder comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I) as described above. Provide a method. In certain embodiments, the cell proliferative disorder is cancer.

  In yet another aspect, the present invention provides the use of a compound of formula (I) as described above for the manufacture of a pharmaceutical composition for the treatment or prevention of cell proliferative disorders. In certain embodiments, the cell proliferative disorder is cancer.

  When a compound of the present invention is administered as a medicament to humans and animals, the compound alone or, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient It can be administered as a pharmaceutical composition containing in combination with a top acceptable carrier.

  Regardless of the chosen route of administration, the compounds of the present invention and / or the pharmaceutical compositions of the present invention that may be used in an appropriate hydrated form are pharmaceutically acceptable by conventional means known to those skilled in the art. Formulated into a dosage form.

  The actual dosage level and duration of administration of the active ingredients in the pharmaceutical composition of the present invention is such that an effective amount of the active ingredient is obtained to achieve the desired therapeutic response for the individual patient, composition and route of administration. It may be changed so that it is not toxic to. Exemplary dose ranges are 0.01-100 mg / kg / day or 0.1-150 mg / kg / day.

  In certain embodiments, the compounds of the invention can be used in combination therapy with conventional cancer chemotherapeutic agents. Conventional treatment methods for leukocytes and other tumors include irradiation, drugs or combinations thereof.

  Determination of a therapeutically effective antiproliferative amount or a prophylactically effective antiproliferative amount of the compound of the present invention can be carried out by using a known method and observing the results obtained in a similar environment by those skilled in the art. As a doctor or veterinarian (advisor). The dosage may vary depending on the patient's requirements, depending on the judgment of the advisor; the severity of the condition being treated and the particular compound used. In determining, but not limited to, a therapeutically effective anti-proliferation amount or dose, and a prophylactically effective anti-proliferation amount or dose; Pharmacodynamic properties and methods and routes of administration thereof; desired duration of treatment; type of mammal; size, age and overall health; specific disease involved; degree of disease, or disease involvement or severity Individual patient response; individual compound administered; method of administration; bioavailability characteristics of the formulation administered; selected dosing regimen; type of combination therapy (ie other combination treatments of compounds of the invention) Many factors are considered by the consulting physician, including drug interactions); and other related environments.

  Treatment can be initiated with less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dose may be divided and administered in portions during the day if desired. The therapeutically effective and prophylactically effective antiproliferative amounts of the compounds of the present invention range from about 0.01 mg / kg / day (milligrams per kg body weight per day) to about 100 mg / kg / day. It is considered to change with the day.

  The preferred dose of the compound for the present invention is the maximum dose that the patient can tolerate and does not cause severe side effects. Illustratively, the compounds of the present invention may be administered at a dose of about 0.01 mg / kg to about 100 mg / kg body weight, about 0.01 mg / kg to about 10 mg / kg body weight, or about 0.1 mg / kg to about 10 mg / kg body weight. Be administered. Ranges in the middle of the above values are also intended to form part of the present invention.

  Unless otherwise noted,% in the following tests and examples is% by weight; parts are parts by weight. Solvent percentages, dilution percentages and concentrations reported in liquid / liquid solutions are each based on volume.

A. Example
Abbreviations and acronyms:
Ac acetyl aq. Aqueous (solution)
br. s Broad singlet (NMR)
cat. Catalytic conc. Concentrated d doublet (NMR)
DCI Direct chemical ionization (MS)
dd Doublet doublet (NMR)
DMF N, N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d ₆ dimethyl sulfoxide-d ₆
EI Electron impact ionization (MS)
equiv. Equivalent (multiple allowed)
ESI Electron injection ionization (MS)
Et ethyl GC-MS Mass spectrometry h coupled with gas chromatography h Time (s)
¹ H-NMR Proton Nuclear Magnetic Resonance Analysis HOAc Acetic Acid HPLC High Performance / High Pressure Liquid Chromatography LC-MS Mass Spectrometry Coupled with Liquid Chromatography m Multiplet (NMR)
Me methyl min min (s)
MS Mass spectrometry m / z Mass / charge ratio NBS N-bromosuccinimide NCS N-chlorosuccinimide NMP N-methylpyrrolidin-2-one of th. Theoretical value (chemical yield)
p-TsOH p-toluenesulfonic acid q quartet (NMR)
R _f TLC retention factor RP reverse phase (HPLC)
rt room temperature _{R t} retention time (HPLC)
s Singlet (NMR)
SEM 2- (Trimethylsilyl) ethoxymethyl sept septet (NMR)
TBAF tetra-n-butylammonium fluoride tBu tert-butyl TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography t triplet (NMR)
v / v volume / volume ratio w / v weight / volume ratio w / w weight / weight ratio

LC-MS and GC-MS methods:
Method 1 (LC-MS):
Instrument: Micromass ZQ with HPLC Waters Alliance 2795; Column: Phenomenex Synergi 2.5u MAX-RP 100A Mercury, 20 mm x 4 mm; Eluent A: 1 liter water + 0.5 mL 50% formic acid, Eluent B: 1 liter acetonitrile +0.5 mL of 50% formic acid; gradient: 90% A for 0.0 minutes → 90% A for 0.1 minutes → 5% A for 3.0 minutes → 5% A for 4.0 minutes → 4.01 minutes 90% A; flow rate: 2 mL / min; oven: 50 ° C .; UV detection: 210 nm

Method 2 (LC-MS):
Equipment: Micromass Quattro Premier with HPLC Waters UPLC Acquity; Column: Thermo Hypersil GOLD 1.9u, 50 mm x 1 mm; Eluent A: 1 L water + 0.5 mL 50% formic acid, Eluent B: 1 L acetonitrile + 0.5 mL 50 Gradient: 90% A for 0.0 minutes → 90% A for 0.1 minutes → 10% A for 1.5 minutes → 10% A for 2.2 minutes; Oven: 50 ° C .; 33 mL / min; UV detection: 210 nm

Method 3 (LC-MS):
Equipment: HPLC Micromass Quattro Micro with Agilent 1100 Series; Column: Thermo Hypersil GOLD 3u, 20 mm x 4 mm; Eluent A: 1 L water + 0.5 mL 50% formic acid, Eluent B: 1 L acetonitrile + 0.5 mL 50% Formic acid; Gradient: 100% A for 0.0 minutes → 10% A for 3.0 minutes → 10% A for 4.0 minutes → 100% A for 4.01 minutes (flow rate 2.5 mL / min) → 5. 100% A for 00 minutes; oven: 50 ° C .; flow rate: 2 mL / min; UV detection: 210 nm

Method 4 (LC-MS):
Equipment: Waters Acquity SQD UPLC System; Column: Waters Acquity UPLC HSS T3 1.8u, 50 mm x 1 mm; Eluent A: 1 L water + 0.25 mL 99% formic acid, Eluent B: 1 L acetonitrile + 0.25 mL 99% formic acid; Gradient: 90% A for 0.0 minutes → 5% A for 1.2 minutes → 5% A for 2.0 minutes; oven: 50 ° C .; flow rate: 0.40 mL / min; UV detection: 210-400 nm

Method 5 (GC-MS):
Equipment: Micromass GCT, GC 6890; Column: Restek RTX-35, 15 mx 200 μm x 0.33 μm; Steady flow of helium: 0.88 mL / min; Oven: 70 ° C; Inlet: 250 ° C; Gradient: 70 ° C, 30 ° C / min → 310 ° C (hold for 3 minutes)

Starting materials and intermediates:
Example 1A
3-Methyl-1H-indazole-5-carbaldehyde

Tetrahydrofuran (600 ml) was cooled to −78 ° C. under an argon atmosphere. At this temperature, a 1.7M solution of tert-butyllithium in n-pentane (200 ml) was added dropwise. After 15 minutes at −78 ° C., a solution of 22.4 g (106.1 mmol) of 5-bromo-3-methyl-1H-indazole in THF (300 ml) was added and the temperature of the solution did not exceed −70 ° C. It was dripped at a speed. The mixture was stirred for 30 minutes and N, N-dimethylformamide (24.5 ml) was added dropwise. After 20 minutes, the cooling bath was removed, stirring was continued for 1 hour, and water (250 ml) was carefully added. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers are washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure to give 18.5 g of crude 3-methyl-1H-indazole-5-carbaldehyde, which is further purified. Used in the next step without.
¹ H-NMR (DMSO-d ₆ ): δ = 13.13 (brs, 1H), 10.01 (s, 1H), 8.40 (s, 1H), 7.81 (d, 1H), 7 .58 (d, 1H), 2.56 (s, 3H) ppm

Example 2A
(2E) -2-[(3-Methyl-1H-indazol-5-yl) methylidene] -3-oxobutanenitrile

3-Methyl-1H-indazole-5-carbaldehyde (Example 1A, 5.0 g, 31.2 mmol), sodium (1Z) -1-cyanoprop-1-en-2-olate (3.61 g, 34. 3 mmol), acetic acid (2.23 ml, 39 mmol) and piperidine (0.31 ml, 3.12 mmol) in dry dichloromethane (250 ml) containing 4 mol molecular sieves were stirred at reflux for 12 hours. After cooling, a precipitate formed and was collected by filtration and washed with saturated aqueous sodium bicarbonate and water. The solid was dissolved in ethanol and the molecular sieve was filtered. The filtrate was concentrated under reduced pressure and the residue was treated with ethyl acetate and saturated aqueous sodium carbonate. The organic layer is washed with water, dried and concentrated under reduced pressure to give the title compound (3.5 g, 50% of theory) as a pale yellow solid that is used in the next step without further purification. It was. LC-MS (Method 1): R _t = 1.32 min; MS (ESIpos): m / z = 226 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 13.18 (brs, 1H), 8.52 (s, 1H), 8.49 (s, 1H), 8.19 (d, 1H) 7.69 (d, 1H), 2.55 (brm, 6H) ppm

Example 3A
3-Iodo-1H-indazole-5-carbaldehyde

1H-indazole-5-carbaldehyde [preparation described in US 2005 / 0227968-A1 (Intermediate 1)] (20 g, 137 mmol) in sodium hydroxide (82 g) dissolved in 1,4-dioxane (640 ml). , 2053 mmol) in water (640 ml). Iodine (43.2 g, 170 mmol) was then added and the mixture was stirred at room temperature for 1 hour. Thereafter, another batch of iodine (43.2 g, 170 mmol) was added and the mixture was again stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give a precipitated solid. Filtration, washing the precipitate with water and drying in phosphorus desiccator over phosphorus oxide for 12 hours under high vacuum gave the title compound (26.6 g, 72% of theory) as a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.81 (s, 1H), 7.74 (d, 1H), 7.40 (d, 1H), 7.32 (dd, 1H) ppm

Example 4A
3-Iodo-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole-5-carbaldehyde

3-Iodo-1H-indazole-5-carbaldehyde (Example 3A, 21.6 g, 79.5 mmol), and cesium carbonate (31.1 g, 95.4 mmol), dissolved in DMF (100 ml), Treated slowly with 2- (trimethylsilyl) ethoxymethyl chloride (15.9 g, 95.4 mmol) at 0 ° C. The mixture was warmed to room temperature and stirring was continued for 12 hours. The solid was then filtered and the filtrate was evaporated to dryness to give the title compound (26.4 g, 82% of theory).
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.22 (s, 1H), 8.26 (d, 1H), 8.09 (dd, 1H), 8.05 (d, 1H) 5.92 (s, 2H), 3.65 (t, 2H), 0.91 (t, 2H), 0.00 (s, 9H) ppm

Example 5A
5- (1,3-Dioxolan-2-yl) -3-iodo-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole

3-iodo-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole-5-carbaldehyde (Example 4A, 6.11 g, 15.2 mmol), ethylene glycol (100 ml) in toluene (100 ml) 2.82 g, 45.6 mmol) and p-toluenesulfonic acid (trace) were heated to reflux overnight using a Dean-Stark trap. After cooling, the mixture was extracted twice with saturated aqueous sodium bicarbonate and washed with brine. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The remaining material was purified by preparative RP-HPLC (acetonitrile / water gradient) to give 3.94 g (58% of theory) of the pure title compound.
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.90 (d, 1H), 7.69 (dd, 1H), 7.63 (s, 2H), 5.87 (s, 2H) 4.23 (m, 2H), 4.09 (m, 2H), 3.62 (t, 2H), 0.89 (t, 2H), 0.00 (s, 9H) ppm

Example 6A
5- (1,3-Dioxolan-2-yl) -3-methoxy-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole

5- (1,3-dioxolan-2-yl) -3-iodo-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole (Example 5A, 300 mg, 0.672 mmol), cesium carbonate (438 mg, 1.344 mmol) and 3,4,7,8-tetramethyl-1,10-phenanthroline (32 mg, 0.134 mmol) in methanol (4 ml) were added to copper iodide. (I) (13 mg, 0.067 mmol) was added. The flask was placed in an ultrasonic bath and argon was bubbled through for 5 minutes. The flask was then sealed and microwaves were heated to 140 ° C. for 2 hours using an irradiator. The reaction mixture was filtered through celite, which was washed with acetonitrile. All seven reaction filtrates at this scale were collected and purified by preparative RP-HPLC (acetonitrile / water gradient) to give 940 mg (57% of theory) of the title compound.
LC-MS (Method 3): R _t = 2.53 min; MS (ESIpos): m / z = 351 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.77 (brs, 1H), 7.73 (d, 1H), 7.59 (dd, 1H), 5.91 (s, 1H) 5.67 (s, 2H), 4.20-4.17 (m, 2H), 4.11 (s, 3H), 4.07-4.04 (m, 2H), 3.61 (t , 2H), 0.89 (t, 2H), 0.01 (s, 9H) ppm

Example 7A
3-methoxy-1H-indazole-5-carbaldehyde

5- (1,3-Dioxolan-2-yl) -3-methoxy-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-indazole (Example 6A, 940 mg, 2. 682 mmol) and ethane-1,2-diamine (805 mg, 13.41 mmol) were added tetrabutylammonium fluoride solution (12.98 ml, 12.98 mmol, 1.0 M in THF). The reaction mixture was heated at 50 ° C. for 3 hours. After this time, tetrabutylammonium fluoride solution (12.98 ml, 12.98 mmol, 1.0 M in THF) was added again and heating was continued for another 12 hours until conversion was complete. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated and the remaining solid was purified by chromatography on silica gel (cyclohexane / ethyl acetate gradient) to give 556 mg (94% of theory) of the intermediate compound, 5- (1,1, 3-Dioxolan-2-yl) -3-methoxy-1H-indazole was obtained [LC-MS (Method 3): R _t = 1.44 min; MS (ESIpos): m / z = 211 (M + H) ⁺ ]. This material was dissolved in ethanol (37 ml), treated with 1N hydrochloric acid (9.4 ml) and heated to 90 ° C. for 30 minutes. After this period, the mixture was evaporated to dryness and the crude aldehyde thus obtained was used in the next step without further purification.
LC-MS (Method 3): R _t = 1.40 min; MS (ESIpos): m / z = 177 (M + H) ⁺

Example 8A
(2E) -2-[(3-Methoxy-1H-indazol-5-yl) methylidene] -3-oxobutanenitrile

3-methoxy-1H-indazole-5-carbaldehyde (Example 7A, 300 mg, 1.704 mmol), sodium (1Z) -1-cyanoprop-1-en-2-olate (151 mg, 1.442 mmol), A mixture of acetic acid (93 μl, 1.639 mmol) and piperidine (11 mg, 0.131 mmol) in dry dichloromethane (10 ml) was refluxed overnight using a water separator. After cooling, a precipitate formed and was removed by filtration. The filtrate thus obtained was concentrated and the residue was purified by preparative RP-HPLC (acetonitrile / water gradient) to give 43 mg (10% of theory) of the title compound.
LC-MS (Method 3): R _t = 1.70 min; MS (ESIpos): m / z = 242 (M + H) ⁺

Example 9A
6-Fluoro-3-methyl-1H-indazole-5-carbaldehyde

5-Bromo-6-fluoro-3-methyl-1H-indazole [WO 2005 / 085227-A1, the preparation described in Example 104c; also available as CAS Registry Number [864773-66-0] 30 g, 131 mmol] in THF (525 ml) was cooled to -45 ° C. A solution of methylmagnesium chloride in THF (3M; 50.2 ml, 151 mmol) was added dropwise at −45 ° C. and the resulting solution was stirred at this temperature for 40 minutes. Using an infusion pump, 2-butyllithium solution (253 ml, 354 mmol, 1.4 M in cyclohexane) was added so that the temperature did not exceed -40 ° C. The resulting mixture was stirred at −40 ° C. for 30 minutes, and then N, N-dimethylformamide (30.2 ml, 393 mmol) was added dropwise while maintaining the temperature at −40 ° C. The resulting mixture was stirred at −40 ° C. for 30 minutes, then warmed to room temperature and slowly poured into 2N hydrochloric acid cooled to 5 ° C. in an 2.8 L volume (ice water bath). The mixture was extracted several times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane and purified by chromatography on silica gel (eluent: pentane / ethyl acetate 6: 4 v / v) to give 19.6 g (78% of theory) of the title compound as a pale yellow solid. Got as.
MS (ESIpos): m / z = 179 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 13.14 (s, 1H), 10.17 (s, 1H), 8.33 (d, 1H), 7.37 (d, 1H) 2.54 (s, 3H) ppm

Example 10A
(2E) -2-[(6-Fluoro-3-methyl-1H-indazol-5-yl) methylidene] -3-oxobutanenitrile

Following the procedure described in Example 2A, 6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 9A, 2.74 g, 15.5 mmol) and sodium (1Z) -1-cyanoprop-1 The title compound was prepared using -en-2-olate (2.6 g (24.8 mmol)) to give 1.6 g (42% of theory) of the crude product which was obtained without further purification. Used in the process.
LC-MS (Method 4): R _t = 0.83 min; MS (ESIpos): m / z = 244 (M + H) ⁺

Example 11A
4,4-difluoro-3-oxobutanenitrile

A flame-dried flask was charged with an n-butyllithium solution (3.8 ml, 6.1 mmol, 1.6 M in hexane) in dry THF (19 ml) under an inert gas atmosphere at -78 ° C. Cooled to. Acetonitrile (0.28 ml, 5.3 mmol) was then added slowly and the resulting mixture was stirred at -70 ° C. for 1 hour. Then ethyl difluoroacetate (0.4 ml, 3.8 mmol) was added slowly over 5 minutes keeping the temperature below -69 ° C. The reaction mixture was stirred at −45 ° C. for 2 hours and then quenched by adding hydrochloric acid (2M, 4.8 ml) while maintaining the temperature below −20 ° C. The resulting clear solution was allowed to warm to room temperature and then concentrated under reduced pressure. The crude product thus obtained (1.0 g, 46% purity, 99% of theory) was stored at −21 ° C. and used in the next step without further purification.
GC-MS (Method 5): R _t = 1.49 min; MS (EIpos): m / z = 119 (M) ⁺

Example 12A
6-Fluoro-1H-indazole-5-carbaldehyde

A slurry of 6-fluoro-1H-indazole-5-carbonitrile [commercially available; EP 1510516-A1 (Preparation 82); 4.8 g, 30 mmol)] in anhydrous toluene (150 ml) to −40 ° C. Cooled down. Under an inert gas atmosphere, diisobutylaluminum hydride solution (48 ml, 72 mmol, 1.5 M in toluene) was added over 30 minutes and the resulting mixture was stirred at 40 ° C. for 3 hours. Ethyl acetate (30 ml) was then added and the mixture was stirred at 40 ° C. for an additional 20 minutes, followed by the dropwise addition of aqueous tartaric acid (1M, 30 ml). The mixture was warmed to 0 ° C. and filtered at this temperature. The filtrate was extracted several times with ethyl acetate and the combined organic phases were then washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product thus obtained (2.60 g, 53% of theory) was used in the next step without further purification.
LC-MS (Method 4): R _t = 0.59 min; MS (ESIpos): m / z = 165 (M + H) ⁺

Example 13A
(2E) -2-[(6-Fluoro-1H-indazol-5-yl) methylidene] -3-oxobutanenitrile

The title compound was 6-fluoro-1H-indazole-5-carbaldehyde (Example 12A, 3.7 g, 80% purity, 18.0 mmol) and sodium (1Z) -1-cyanoprop-1-en-2-olate. (2.08 g, 19.84 mmol) was prepared analogously to the procedure described in Example 2A to give 2.5 g (61% of theory) of the product without further purification. Used in the process.
LC-MS (Method 2): R _t = 0.71 min; MS (ESIpos): m / z = 230 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 13.90 (s, 1H), 8.59 (s, 1H), 8.46 (s, 1H), 8.23 (d, 1H) 7.80 (d, 1H), 2.5 (brs, 3H) ppm

Example 14A
1- (5-Bromo-2-fluorophenyl) -1-propanol

To a solution of 5-bromo-2-fluorobenzaldehyde (15 g, 73.9 mmol) in diethyl ether (100 ml) at 0 ° C., ethylmagnesium bromide solution (27.1 ml, 81.3 mmol, 3M in diethyl ether). ) Was added slowly. After stirring at 0 ° C. for 3 hours, water (20 ml) was carefully added and a white precipitate formed. The solid was filtered and washed with tert-butyl methyl ether. The combined filtrate was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude title compound thus obtained (16.1 g, 93% of theory) was used in the next step without further purification.
GC-MS (Method 5): R _t = 4.54 min; MS (EIpos): m / z = 232 (M) ⁺

Example 15A
1- (5-Bromo-2-fluorophenyl) -1-propanone

1- (5-Bromo-2-fluorophenyl) -1-propanol (Example 14A, 10 g, 42.9 mmol), neutral alumina (8.75 g, 85.8 mmol) and pyridinium chlorochromate (18. A mixture of 5 g, 85.8 mmol) in dichloromethane (100 ml) was stirred at room temperature for 4 hours. The mixture was then filtered through silica gel (0.06-0.2 mm, 200 g), which was washed thoroughly with dichloromethane (1000 ml). The combined filtrate was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude title compound thus obtained (8.6 g, 87% of theory) was used in the next step without further purification.
GC-MS (Method 5): R _t = 4.30 min; MS (EIpos): m / z = 230 (M) ⁺

Example 16A
5-Bromo-3-ethyl-1H-indazole

A solution of 1- (5-bromo-2-fluorophenyl) -1-propanone (Example 15A, 7.50 g, 32.5 mmol) in 1-methyl-2-pyrrolidinone (NMP; 100 ml) was hydrazine hydrate. (3.25 g, 3.16 ml, 64.9 mmol) and stirred at reflux for 16 hours. After cooling, the mixture was poured into a mixture of ice and water. The precipitate was collected by filtration and washed thoroughly with water to give 4.56 g (62% of theory) of the title compound as an off-white solid.
LC-MS (Method 4): R _t = 1.00 min; MS (ESIpos): m / z = 225 (M + H) ⁺

Example 17A
3-ethyl-1H-indazole-5-carbaldehyde

A solution of 5-bromo-3-ethyl-1H-indazole (Example 16A, 6.90 g, 30.7 mmol) in THF (300 ml) was cooled to -78 ° C. At this temperature, tert-butyllithium solution (63.1 ml, 107 mmol, 1.7 M in n-pentane) was added slowly. The mixture was stirred at −78 ° C. for 30 minutes and N, N-dimethylformamide (80.0 ml) was added slowly. The cooling bath was removed and stirring was continued until room temperature was reached. Then water (250 ml) was carefully added. The mixture was extracted several times with ethyl acetate (500 ml). The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure to give 4.5 g (84% of theory) of the crude title compound without further purification. Used in the next step.
LC-MS (Method 4): R _t = 0.73 min; MS (ESIpos): m / z = 175 (M + H) ⁺

Example 18A
(2E) -2-[(3-Ethyl-1H-indazol-5-yl) methylidene] -3-oxobutanenitrile

3-ethyl-1H-indazole-5-carbaldehyde (Example 17A, 0.50 g, 2.87 mmol), sodium (1Z) -1-cyanoprop-1-en-2-olate (0.33 g, 3. 16 mmol), acetic acid (0.21 ml, 3.6 mmol) and piperidine (0.028 ml, 0.29 mmol) in dry dichloromethane (25 ml) containing 4 mol molecular sieves were stirred at reflux for 16 hours. Upon cooling, a precipitate formed which was collected by filtration and washed with saturated aqueous sodium bicarbonate and water. The solid was dissolved in ethanol, and the molecular sieve was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was treated with ethyl acetate and saturated aqueous sodium carbonate. The organic layer was washed with water, dried and concentrated under reduced pressure to give the title compound (0.60 g, 88% of theory) as a pale yellow solid that was used in the next step without further purification. It was.
LC-MS (Method 1): R _t = 1.50 min; MS (ESIpos): m / z = 240 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 13.17 (brs, 1H), 8.59 (s, 1H), 8.51 (s, 1H), 8.17 (d, 1H) 7.67 (d, 1H), 2.97 (q, 2H), 2.55 (brm, 3H), 1.36 (t, 3H) ppm

Preparation example:
Example 1
3,6-Dimethyl-4- (3-methyl-1H-indazol-5-yl) -4,7-dihydroisoxazolo [5,4-b] pyridine-5-carbonitrile

(2E) -2-[(3-Methyl-1H-indazol-5-yl) methylidene] -3-oxobutanenitrile (Example 2A, 180 mg, 0.80 mmol) and 3-methyl-1,2-iso A mixture of oxazol-5-amine (78 mg, 0.80 mmol) in propan-2-ol (3.6 ml) was stirred at reflux temperature overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative RP-HPLC (acetonitrile / water + 0.1% TFA gradient) to give 153 mg (63% of theory) of racemic. The title compound was obtained.
LC-MS (Method 2): R _t = 0.90 min; MS (ESIpos): m / z = 306 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.64 (brs, 1H), 10.79 (s, 1H), 7.56 (s, 1H), 7.43 (d, 1H) 7.19 (d, 1H), 4.98 (s, 1H), 2.48 (s, 3H), 2.13 (s, 3H), 1.69 (s, 3H) ppm

Example 2
6-Methyl-4- (3-methyl-1H-indazol-5-yl) -4,7-dihydroisoxazolo [5,4-b] pyridine-5-carbonitrile

(2E) -2-[(3-Methyl-1H-indazol-5-yl) methylidene] -3-oxobutanenitrile (Example 2A, 50 mg, 0.22 mmol) and 1,2-oxazol-5-amine A mixture of (19 mg, 0.22 mmol) in propan-2-ol (1.0 ml) was stirred at reflux temperature overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative RP-HPLC (gradient of acetonitrile / water + 0.1% TFA) to give 45 mg (69% of theory) of racemate. To give the title compound.
LC-MS (Method 2): R _t = 0.85 min; MS (ESIpos): m / z = 292 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.63 (brs, 1H), 10.91 (s, 1H), 8.14 (s, 1H), 7.55 (s, 1H) 7.43 (d, 1H), 7.19 (d, 1H), 5.02 (s, 1H), 2.48 (s, 3H), 2.16 (s, 3H) ppm

Example 3
4- (3-Methoxy-1H-indazol-5-yl) -6-methyl-4,7-dihydroisoxazolo [5,4-b] pyridine-5-carbonitrile

(2E) -2-[(3-Methoxy-1H-indazol-5-yl) methylidene] -3-oxobutanenitrile (Example 8A, 43 mg, 0.178 mmol) was converted to 1,2-oxazol-5-amine. And processed according to the procedure described in Example 2. The crude product was purified by preparative RP-HPLC (acetonitrile / water gradient) to give 3 mg (5% of theory) of the racemic title compound.
LC-MS (Method 3): R _t = 1.62 min; MS (ESIpos): m / z = 308 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 11.91 (brs, 1H), 10.91 (brs, 1H), 8.15 (s, 1H), 7.40 (brs, 1H) 7.34 (d, 1H), 7.23 (dd, 1H), 4.99 (s, 1H), 3.99 (s, 3H), 2.48 (s, 3H), 2.16 ( s, 3H) ppm

Example 4
4- (6-Fluoro-3-methyl-1H-indazol-5-yl) -3,6-dimethyl-4,7-dihydroisoxazolo [5,4-b] pyridine-5-carbonitrile

(2E) -2-[(6-Fluoro-3-methyl-1H-indazol-5-yl) methylidene] -3-oxobutanenitrile (Example 10A, 100 mg, 0.411 mmol) and 3-methyl-1 , 2-isoxazol-5-amine (40.3 mg, 0.411 mmol) in propan-2-ol (2.0 ml) was stirred at reflux temperature overnight. Acetic acid (0.2 ml) was added and the mixture was stirred for an additional hour at reflux temperature. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative RP-HPLC (gradient of methanol / water + 0.1% TFA) to yield 19.8 mg (15% of theory). The racemic title compound was obtained.
LC-MS (Method 4): R _t = 0.79 min; MS (ESIpos): m / z = 324 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.71 (brs, 1H), 10.82 (s, 1H), 7.60 (d, 1H), 7.23 (d, 1H) 5.18 (s, 1H), 2.46 (s, 3H), 2.14 (s, 3H), 1.72 (s, 3H) ppm

Example 5
6- (Difluoromethyl) -4- (6-fluoro-3-methyl-1H-indazol-5-yl) -3-methyl-4,7-dihydroisoxazolo [5,4-b] pyridine-5- Carbonitrile

6-Fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 9A, 200 mg, 1.122 mmol), 4,4-difluoro-3-oxobutanenitrile (Example 11A, 147 mg, 1.234) Mmol), acetic acid (0.08 ml, 0.70 mmol) and piperidine (12 μl, 0.056 mmol) in dry dichloromethane (4 ml) containing 4 mol molecular sieves were stirred at reflux for 12 hours. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 2-propanol (2 ml) and acetic acid (1 ml) under argon. 3-Methyl-1,2-isoxazol-5-amine (110 mg, 1.122 mmol) was added and the solution was stirred at reflux for 12 hours. Upon cooling, the mixture was evaporated to dryness and the residue was dissolved in THF (4 ml) containing 4Å molecular sieves. Tetra-n-butylammonium fluoride solution (TBAF, 1N in THF, 4.5 ml) was added and the mixture was stirred at 55 ° C. for 12 hours. Again, TBAF solution (1N in THF, 4.5 ml) was added and the mixture was stirred at 55 ° C. for a further 12 hours. Upon cooling, the mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed several times with brine and then with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (methanol / water + 0.1% TFA gradient) to give 29 mg (7% of theory) of the racemic title compound.
LC-MS (Method 4): R _t = 0.83 min; MS (ESIpos): m / z = 360 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.77 (brs, 1H), 11.58 (s, 1H), 7.69 (d, 1H), 7.28 (d, 1H) 6.93 (t, 1H, ² JH _{, F} = 52 Hz), 5.38 (s, 1H), 2.47 (s, 3H), 1.74 (s, 3H) ppm

Example 6
4- (3-Ethyl-1H-indazol-5-yl) -3,6-dimethyl-4,7-dihydroisoxazolo [5,4-b] pyridine-5-carbonitrile

(2E) -2-[(3-Ethyl-1H-indazol-5-yl) methylidene] -3-oxobutanenitrile (Example 18A, 100 mg, 0.42 mmol) was prepared according to the procedure described in Example 2. -Treated with methyl-1,2-oxazol-5-amine. The crude product was purified by preparative RP-HPLC (methanol / water + 0.1% TFA gradient) to give 51 mg (38% of theory) of the racemic title compound.
LC-MS (Method 4): R _t = 0.84 min; MS (ESIpos): m / z = 320 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.63 (brs, 1H), 10.79 (brs, 1H), 7.59 (s, 1H), 7.44 (d, 1H) 7.17 (dd, 1H), 4.98 (s, 1H), 2.92 (q, 2H), 2.14 (s, 3H), 1.70 (s, 3H), 1.31 ( t, 3H) ppm

Example 7
4- (6-Fluoro-1H-indazol-5-yl) -3,6-dimethyl-4,7-dihydroisoxazolo [5,4-b] pyridine-5-carbonitrile

(2E) -2-[(6-Fluoro-1H-indazol-5-yl) methylidene] -3-oxobutanenitrile (Example 13A, 100 mg, 0.44 mmol) was prepared according to the procedure described in Example 2. -Treated with methyl-1,2-oxazol-5-amine. The crude product was purified by preparative RP-HPLC (methanol / water + 0.1% TFA gradient) to give 55 mg (41% of theory) of the racemic title compound.
LC-MS (Method 4): R _t = 0.78 min; MS (ESIpos): m / z = 310 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 13.15 (brs, 1H), 10.87 (brs, 1H), 8.09 (s, 1H), 7.68 (d, 1H) 7.35 (dd, 1H), 5.19 (s, 1H), 2.14 (s, 3H), 1.73 (s, 3H) ppm

Example 8
6- (Difluoromethyl) -3-methyl-4- (3-methyl-1H-indazol-5-yl) -4,7-dihydroisoxazolo [5,4-b] pyridine-5-carbonitrile

3-methyl-1H-indazole-5-carbaldehyde (Example 1A, 150 mg, 0.936 mmol), 4,4-difluoro-3-oxobutanenitrile (Example 11A, 111 mg, 0.936 mmol), acetic acid A mixture of (0.067 ml, 1.17 mmol) and piperidine (9.3 μl, 0.094 mmol) in dry dichloromethane (4 ml) containing 4 mol molecular sieves was stirred at reflux for 12 hours. The mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 2-propanol (2 ml) and acetic acid (1 ml) under argon. 3-Methyl-1,2-isoxazol-5-amine (95 mg, 0.936 mmol) was added and the solution was stirred at reflux for 30 minutes. Upon cooling, the mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate and water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (methanol / water + 0.1% TFA gradient) to give 16 mg (5% of theory) of the racemic title compound.
LC-MS (Method 4): R _t = 0.82 min; MS (ESIpos): m / z = 342 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.70 (s, 1H), 11.55 (s, 1H), 7.60 (s, 1H), 7.48 (d, 1H) 7.21 (d, 1H), 6.93 (t, 1H, ² JH _{, F} = 52 Hz), 5.19 (s, 1H), 2.50 (s, 3H), 1.71 (s, 3H) ppm

B. Assessment of Biological Activity Demonstration of the activity of the compounds of the present invention can be accomplished through in vitro, ex vivo and in vivo assays that are well known in the art. For example, the following assay may be used to demonstrate the activity of the compounds of the present invention.

c-Met receptor tyrosine kinase activity assay (NADH reading):
Recombinant human c-Met protein (Invitrogen, Carlsbad, California, USA) is used. The peptide KKKSPGEYVNIEFG (JPT, Germany) is used as a substrate for the kinase reaction. For the assay, a 51-fold concentrated solution (1 μL) of test compound in DMSO is pipetted into a 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). 25 [mu] L c-Met (final concentration: 30 nM) and pyruvate kinase / lactate dehydrogenase (Roche Diagnostics, Mannheim, Germany; final concentration: 8 mg / L) assay buffer [3- (N-morpholino) propanesulfonic acid (MOPS) ), 50 mM, pH 7; MgCl2, 10 mM; bovine serum albumin (BSA), 0.01%; Triton X100, 0.01%; DTT, 2 mM], and the mixture is incubated at room temperature for 5 minutes. Then 25 μL adenosine triphosphate (ATP, final concentration: 30 μM), substrate (final concentration: 100 μM), nicotinamide adenine dinucleotide (NADH, final concentration: 50 μM) and dithiothreitol (DTT, final concentration: 2 mM) The kinase reaction is initiated by adding a solution in the assay buffer and the resulting mixture is allowed to incubate at 32 ° C. for a reaction time of 100 minutes.

Thereafter, the amount of phosphate substrate is assessed by measuring the decrease in NADH fluorescence. Therefore, the fluorescence emission at 465 nm after excitation at 340 nm is measured with a fluorescence reader such as Tecan Ultra (Tecan, Mannedorf, Switzerland). Data are normalized (enzyme reaction without inhibitor = 0% inhibition; no enzyme but with all other assay components = 100% inhibition). Usually, the test compound is placed on the same microtiter plate in 9 different concentrations (10 μM, 3.1 μM, 1.0 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM) in the range of 10 μM to 1 nM. , 0.003 μM, 0.001 μM; a series of dilutions prepared by serial dilutions of 1: 3 prior to assaying at the 51-fold concentrated stock solution level) IC ₅₀ values are calculated using the following software.

When tested in this assay, compounds of the present invention showed the ability to inhibit c-Met tyrosine kinase activity with IC ₅₀ values less than 10 μM, preferably less than 1 μM.

Some representative IC ₅₀ values are listed in the following table:

Homogeneous time-resolved fluorescence assay of c-Met receptor tyrosine kinase (another format)
N-terminal His6-tagged set of human c-Met (amino acids 960-1390) expressed in insect cells (SF21) and purified by Ni-NTA affinity chromatography and continuous size exclusion chromatography (Superdex 200) An alternative kinase domain is used. Alternatively, commercially available c-Met (Millipore) can also be used. Biotinylated poly-Glu, Tyr (4: 1) copolymer (No. 61GT0BLC, Cis Biointernational, Marcoule, France) is used as a substrate for the kinase reaction.

  For the assay, a 100-fold concentrated solution of test compound in DMSO (50 nL) is pipetted into a black low volume 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). 2 μL of c-Met assay buffer [25 mM Hepes / NaOH, pH 7.5; 5 mM MgCl 2; 5 mM MnCl 2; 2 mM dithiothreitol; 0.1% (v / v) Tween 20 (Sigma); 0.1% ( w / v) Bovine Serum Albumin] is added and the mixture is incubated for 15 minutes at 22 ° C. to pre-couple the test compound to the enzyme and initiate the kinase reaction. Then, in assay buffer, 3 μL adenosine triphosphate (ATP, 16.7 μM; final concentration in 5 μL assay volume is 10 μM) and substrate (2.27 μg / mL, final concentration in 5 μL assay volume is 1.). 36 μg to 30 nM) is added to initiate the kinase reaction and the resulting mixture is allowed to incubate at 22 ° C. for a reaction time of 30 minutes. The concentration of c-Met in the assay is adjusted according to the activity of the enzyme by the lot, suitably so that the assay is in the linear range: typically the enzyme concentration is about 0.03 nM (5 μL The final concentration in the assay volume) is selected. HTRF detection reagents [40 nM Streptavidin XLent and 2.4 nM PT66-Eu-chelate in aqueous EDTA solution [100 mM EDTA in 50 mM HEPES / NaOH, pH 7.5, 0.2% (w / v) bovine serum albumin] The reaction is stopped by adding Europium-chelate labeled anti-phosphotyrosine antibody (Perkin-Elmer)] solution (5 μL). .

The resulting mixture is incubated at 22 ° C. for 1 hour to allow the biotinylated phosphopeptide to bind to streptavidin-XLent and PT66-Eu-chelate. Thereafter, the amount of phosphorylated substrate is assessed by measuring the resonance energy transfer from PT66-Eu-chelate to streptavidin-XLent. Therefore, the fluorescence emission at 620 nm and 665 nm after excitation at 340 nm is measured with an HTRF reader such as Rubystar (BMG Labtechnologies, Offenburg, Germany) or Viewlux (Perkin-Elmer). The proportion of emission at 665 nm and 620 nm is taken as a measure of the amount of phosphorylated substrate. Data are normalized (enzyme reaction without inhibitor = 0% inhibition; no enzyme but with all other assay components = 100% inhibition). Typically, test compounds are placed on the same microtiter plate in 10 different concentrations (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2 nM) in the range of 20 μM to 1 nM. 3.1 nM and 1 nM; a series of dilutions prepared by serial dilutions of 1: 3 prior to assaying at the level of 100-fold concentrated stock solution) and tested in-house software twice at each concentration Calculate IC ₅₀ values by 4-parameter-fit using.

When tested in this assay, compounds of the present invention showed the ability to inhibit c-Met tyrosine kinase activity with IC ₅₀ values less than 10 μM, preferably less than 1 μM.

Some representative IC ₅₀ values are listed in the following table:

Phospho-c-Met assay:
This procedure was performed in a cell-based ELISA-like assay [Meso Scale Discovery (MSD), Gaithersburg, MD, USA] using MKN-45 tumor cells (gastric cancer cells, obtained from ATCC) without stimulating growth factors. is there. On day 1, the cells are plated in full growth medium in a 96-well plate (10000 cells / well). On the second day, 2 hours after drug treatment in serum-free medium, cells are washed and then lysed (60 μl / well, using MSD recommended lysis buffer) and frozen at −80 ° C. On the second day, MSD blocking solution A also blocks non-specific antibody binding sites on MSD phospho-Met plates overnight at 4 ° C. On day 3, the frozen lysate was thawed on ice and washed once with Tris-buffered saline + 0.05% Tween 20 (TBST), then 25 μl lysate was transferred to an MSD phospho-Met plate and shaken for 1 hour Let After removal of unbound protein, Sulfa-TAG anti-Met antibody from MSD is added to the plate at a final concentration of 5 nM in antibody dilution buffer (diluted according to MSD protocol) and shaken for 1 hour. . The plate is then washed 3 times with TBST buffer and 1 × MSD read buffer is added. The plate is then read with an MSD Discovery workstation device. Raw data, including 10 μM control compound wells (minimum signal) and DMSO wells without drug treatment (maximum signal), are entered into the Analyze 5 program to determine IC ₅₀ values.

Cellular phospho-c-Met assay:
Human gastric adenocarcinoma cells (MKN45, obtained from ATCC) seeded in 384-well microtiter plates are incubated with 5% CO ₂ in 25 μl of full growth medium at 37 ° C. for 24 hours. On day 2, cells are washed and lysed 2 hours after drug treatment in serum-reducing medium containing 0.1% FCS. After washing the lysate once with Tris buffered saline + 0.05% Tween 20 (TBST), it was pre-conjugated to BSA with c-Met capture antibody [obtained from Mesoscale Discovery (MSD), Gaithersburg, MD, USA]. Transfer to blocking plate and shake for 1 hour. According to the MSD protocol, Sulfa-TAG anti-phospho-c-Met detection antibody is added to the plate at a final concentration of 5 nM in antibody dilution buffer and shaken for 1 hour at room temperature. The wells are washed with Tris buffer, 1x reading buffer is added, and the plate is measured with a Sector Imager 6000 (obtained from Mesoscale). IC ₅₀ values are calculated from dose response curves using Marquardt-Levenberg-Fit.

In vitro tumor cell proliferation assay:
The adherent tumor cell proliferation assay used to test the compounds of the present invention is Promega [BA Cunningham, “A Growing Issue: Cell Proliferation Assays. Modern kits ease quantification of cell growth”, The Scientist 2001, 15 (13), 26; Reading on a device called Cell Titre-Glo developed by SP Crouch et al., “The use of ATP bioluminescence as a measure of cell proliferation and cytotoxicity”, Journal of Immunological Methods 1993, 160, 81-88]. including. The generated luminescent signal corresponds to the amount of ATP present, which is directly proportional to the number of metabolically active (proliferating) cells.

H460 cells (lung cancer, obtained from ATCC) are plated into 96-well plates at 3000 cells / well in complete medium containing 10% fetal calf serum and incubated at 37 ° C. for 24 hours. 24 hours after plating, test compounds are added over a range of final concentrations from 10 nM to 20 μM in serial dilutions with 0.2% final concentration of DMSO. After adding the test compound, the cells are incubated for 72 hours at 37 ° C. in complete growth medium. On the fourth day, the cells are lysed using the Promega Cell Titre-Glo Luminescent® Assay Kit, 100 μl of substrate / buffer mixture is added to each well, mixed and incubated for 8 minutes at room temperature. The sample is read with a luminometer and the amount of ATP present in the cell lysate from each well is measured, which corresponds to the number of viable cells in that well. The value read in the 24 hour incubation is subtracted as day 0. Linear regression analysis can be used to measure IC ₅₀ values and this assay can be used to determine the concentration of drug that inhibits cell growth by 50%. This protocol applies to a variety of cell lines of interest, including but not limited to CAKI-1, MNK-45, GTL-16, HCC2998, K562, H441, K812, MEG01, SUP15 and HCT116. obtain.

  Although the present invention has been disclosed in connection with specific embodiments, it is apparent that other embodiments and modifications of the present invention can be devised by those skilled in the art without departing from the spirit and scope of the present invention. It is. The claims are to be construed to include such embodiments and equivalent variations.

C. Examples related to pharmaceutical compositions The pharmaceutical compositions of the present invention may be described as follows:
Sterile intravenous solution:
A 5 mg / ml solution of the desired compound of the present invention can be prepared by using sterile water for injection and adjusting the pH if necessary. To administer the solution, it is diluted to 1-2 mg / ml with sterile 5% dextrose and administered as an intravenous infusion over about 60 minutes.

Lyophilized powder for intravenous administration:
A sterile preparation was prepared with (i) 100-1000 mg of the desired compound of the present invention as lyophilized powder, (ii) 32-327 mg / ml sodium citrate, and (iii) 300-3000 mg dextran 40. obtain. The formulation is reconstituted to a concentration of 10 to 20 mg / ml using sterile injectable saline or 5% dextrose and further diluted to 0.2 to 0.4 mg / ml with saline or 5% dextrose for 15-60 minutes. Administered as either an intravenous bolus or intravenous infusion.

Intramuscular suspension:
Solutions or suspensions containing the following ingredients may be prepared for intramuscular injection:
50 mg / ml of the desired water-insoluble compound of the present invention; 5 mg / ml sodium carboxymethylcellulose; 4 mg / ml TWEEN 80; 9 mg / ml sodium chloride; 9 mg / ml benzyl alcohol.

Hard shell capsule:
Multiple unit capsules are prepared by filling each regular two-piece hard gelatin capsule with 100 mg powdered active ingredient, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate.

Soft gelatin capsule:
Prepare a mixture of active ingredients in digestible oil such as soybean oil, cottonseed oil or olive oil and inject the mixture into melted gelatin by means of a transfer pump to form a soft gelatin capsule containing 100 mg of the active ingredient . The capsule is washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible drug mixture.

tablet:
Numerous routine manipulations have resulted in a dosage unit containing 100 mg active ingredient, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch, and 98.8 mg lactose. Prepare tablets. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve appearance and stability, or delay absorption.

Claims (16)

Formula (I):

(I)
[Where:
R ¹ is selected from the group consisting of hydrogen, chloro, bromo, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl and phenyl, wherein (i) the (C ₃ -C ₇₎ - cycloalkyl and phenyl, fluoro, chloro, bromo, difluoromethyl, _{trifluoromethyl, (C} 1 -C ₄₎ - alkyl, hydroxy, difluoromethoxy, _{trifluoromethoxy, (C} 1 -C ₄₎ - alkoxy , amino, mono - _(C 1 -C ₄₎ - alkylamino, di - _(C 1 -C ₄₎ - _{alkylamino, (C} 3 -C ₆₎ - cycloalkyl and 4- to 6-membered heterocycloalkyl Optionally substituted with 1 or 2 substituents independently selected from the group consisting of
Wherein the (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, mono- (C ₁ -C ₄ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino substituted The alkyl group of the group may likewise be substituted with hydroxy or (C ₁ -C ₄ ) -alkoxy, and (ii) the (C ₁ -C ₆ ) -alkyl is fluoro, trifluoromethyl, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino, di - _(C 1 -C ₄₎ - _{alkylamino, (C} 3 -C ₇₎ - cycloalkyl Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of phenyl, 4- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl,
Wherein the (C ₃ -C ₇ ) -cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl substituents are likewise fluoro, chloro, bromo, difluoro methyl, _{trifluoromethyl, (C} 1 -C ₄₎ - alkyl, oxo, hydroxy, difluoromethoxy, _{trifluoromethoxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkyl Optionally substituted with 1 or 2 residues independently selected from the group consisting of amino and di- (C ₁ -C ₄ ) -alkylamino, or R ¹ is of the formula —NR ^6A R ^6B or a group represented by -OR ^7, wherein R ^6A and ^{R 6B} is _{hydrogen, (C} 1 -C ₆₎ - _{alkyl, (C} 3 -C ₇₎ - cycloalkyl and It is independently selected from the group consisting of 4- to 7-membered heterocycloalkyl, wherein (i) the (C 3 _-C 7) _- heterocycloalkyl cycloalkyl and 4- to 7-membered, fluoro , difluoromethyl, _{trifluoromethyl, (C} 1 -C ₄₎ - alkyl, oxo, hydroxy, difluoromethoxy, _{trifluoromethoxy, (C} 1 -C ₄₎ - alkoxy, amino, mono _- (C 1 _-C 4) - alkylamino and di - (C 1 _-C 4) _- independently from the group consisting of alkylamino may be substituted by 1 or 2 substituents selected, and (ii) the (C ₁ - C ₆₎ - alkyl, fluoro, trifluoromethyl, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino , Di- (C ₁ -C ₄ ) -alkylamino, (C ₃ -C ₇ ) -cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl Optionally substituted with 1, 2 or 3 substituents selected more independently,
Wherein the (C ₃ -C ₇ ) -cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl substituents are likewise fluoro, chloro, bromo, difluoromethyl, _{trifluoromethyl, (C} 1 -C ₄₎ - alkyl, oxo, hydroxy, difluoromethoxy, _{trifluoromethoxy, (C} 1 -C ₄₎ - alkoxy, amino, mono _- (C 1 _-C 4) _- Optionally substituted with 1 or 2 residues independently selected from the group consisting of alkylamino and di- (C ₁ -C ₄ ) -alkylamino, or R ^6A and R ^6B are the bonds Together with a nitrogen atom to form a 4- to 7-membered heterocycloalkyl ring, wherein the ring is another ring heterogen selected from N, O and S May contain, _{fluoro, (C} 1 -C ₄₎ - alkyl, oxo, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino, di - Optionally substituted with 1 or 2 substituents independently selected from the group consisting of (C ₁ -C ₄ ) -alkylamino and (C ₃ -C ₆ ) -cycloalkyl,
R ⁷ is selected from the group consisting of (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl and 4- to 7-membered heterocycloalkyl, wherein (i) the (C ₃ -C ₇₎ - heterocycloalkyl cycloalkyl and 4- to 7-membered, fluoro, difluoromethyl, _{trifluoromethyl, (C} 1 -C ₄₎ - alkyl, oxo, hydroxy, difluoromethoxy, trifluoromethoxy, 1 or 2 independently selected from the group consisting of (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino And (ii) the (C ₁ -C ₆ ) -alkyl may be fluoro, trifluoromethyl, hydroxy, (C ₁ -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino, di - _(C 1 -C ₄₎ - _{alkylamino, (C} 3 -C ₇₎ - cycloalkyl, phenyl, 4- to to 7 Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of -membered heterocycloalkyl and 5- or 6-membered heteroaryl;
Wherein the (C ₃ -C ₇ ) -cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl substituents are likewise fluoro, chloro, bromo, difluoromethyl, _{trifluoromethyl, (C} 1 -C ₄₎ - alkyl, oxo, hydroxy, difluoromethoxy, _{trifluoromethoxy, (C} 1 -C ₄₎ - alkoxy, amino, mono _- (C 1 _-C 4) _- Optionally substituted with 1 or 2 residues independently selected from the group consisting of alkylamino and di- (C ₁ -C ₄ ) -alkylamino;
R ² is hydrogen, fluoro, chloro or methyl;
R ³ is hydrogen, methyl, difluoromethyl, trifluoromethyl or ethyl;
R ⁴ is selected from the group consisting of (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein (i) the (C ₃ -C ₇ ) -cycloalkyl, phenyl and 5- or 6-membered heteroaryl are fluoro, chloro, cyano, difluoromethyl, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, hydroxy, difluoromethoxy, Independently selected from the group consisting of trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino that 1 or may be substituted by two substituents, and (ii) the (C 1 _-C 6) _- alkyl, fluoro atom up to three or tri Ruoromechiru, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino, di - _(C 1 -C ₄₎ - _alkylamino, (C 3 _-C 7) - Optionally substituted with 1 or 2 substituents independently selected from the group consisting of cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl,
Where the alkyl groups of the (C ₁ -C ₄ ) -alkoxy, mono- (C ₁ -C ₄ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino substituents are fluoro atom up to three or trifluoromethyl, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino, di _- (C 1 _-C 4) _- Optionally substituted with 1 or 2 residues independently selected from the group consisting of alkylamino and 4- to 7-membered heterocycloalkyl,
The (C ₃ -C ₇ ) -cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl and 5- or 6-membered heteroaryl groups are likewise fluoro, chloro, cyano, difluoromethyl, tri _{fluoromethyl, (C} 1 -C ₄₎ - alkyl, oxo, hydroxy, difluoromethoxy, _{trifluoromethoxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino and di -(C ₁ -C ₄ ) -alkylamino optionally substituted with 1 or 2 residues independently selected from the group consisting of, and R ⁵ is hydrogen, (C ₁ -C ₄ )- Alkyl or cyclopropyl]
Or a pharmaceutically acceptable salt, hydrate and / or solvate thereof. R ¹ is selected from the group consisting of hydrogen, (C ₁ -C ₆ ) -alkyl and (C ₃ -C ₆ ) -cycloalkyl, wherein (i) the (C ₃ -C ₆ ) -cycloalkyl is Fluoro, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) optionally substituted with 1 or 2 substituents independently selected from the group consisting of 4-alkylamino and 4- to 6-membered heterocycloalkyl, and (ii) the (C _1- C ₆₎ - alkyl, fluoro, trifluoromethyl, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino, di _- (C 1 _-C 4) _- Alkylamino _(C 3 -C ₆₎ - cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- or 6-membered one, two or three substituents independently selected from the group consisting of heteroaryl May be replaced with
Wherein the (C ₃ -C ₆ ) -cycloalkyl, 4- to 6-membered heterocycloalkyl and 5- or 6-membered heteroaryl substituents are likewise fluoro, chloro, difluoromethyl, tri _{fluoromethyl, (C} 1 -C ₄₎ - alkyl, oxo, _{hydroxy, (C} 1 -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino and di - _(C 1 -C ₄ ) -Alkylamino may be substituted with 1 or 2 residues independently selected from the group consisting of: or R ¹ is a group of formula —OR ⁷ where R ⁷ is (C ₁ -C ₆₎ - alkyl and _(C 3 -C ₆₎ - is selected from the group consisting of cycloalkyl, wherein (i) the _(C 3 -C ₆₎ - cycloalkyl, fluoro, trifluoromethyl, (C ₁ -C ₄₎ - alkyl, _{hydroxy, (C} 1 -C ₄₎ - from the group consisting of alkylamino - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino and di - _(C 1 -C ₄₎ Optionally substituted with one or two independently selected substituents, and (ii) the (C ₁ -C ₆ ) -alkyl is fluoro, trifluoromethyl, hydroxy, (C ₁ -C ₄₎ - alkoxy, amino, mono - _(C 1 -C ₄₎ - alkylamino, di - _(C 1 -C ₄₎ - _{alkylamino, (C} 3 -C ₆₎ - cycloalkyl and 4- to 6-membered Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of
Wherein the (C ₃ -C ₆ ) -cycloalkyl and 4- to 6-membered heterocycloalkyl substituents are likewise fluoro, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, oxo, ₁ independently selected from the group consisting of hydroxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino Or may be substituted with 2 residues,
R ² is hydrogen or fluoro,
R ³ is hydrogen, methyl, difluoromethyl or trifluoromethyl;
R ⁴ is selected from the group consisting of (C ₁ -C ₄ ) -alkyl, cyclopropyl, phenyl and pyridyl, wherein (i) said cyclopropyl is independently from the group consisting of fluoro, trifluoromethyl and methyl Optionally substituted with one or two selected substituents,
(Ii) The phenyl and pyridyl are substituted with 1 or 2 substituents independently selected from the group consisting of fluoro, chloro, cyano, difluoromethyl, trifluoromethyl and (C ₁ -C ₄ ) -alkyl. And (iii) the (C ₁ -C ₄ ) -alkyl is up to 3 fluoro atoms, or (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) substituted with 1 or 2 substituents independently selected from the group consisting of -alkylamino, di- (C ₁ -C ₄ ) -alkylamino and 4- to 6-membered heterocycloalkyl You can,
Here, the alkyl group of the (C ₁ -C ₄ ) -alkoxy substituent is likewise up to 3 fluoro atoms, or (C ₁ -C ₄ ) -alkoxy, amino, mono- (C _1- C ₄₎ - alkylamino, di _- (C 1 _-C 4) - substituted with alkylamino and 4 to one or two residues independently selected from the group consisting of 6-membered heterocycloalkyl You may,
Here, the 4- to 6-membered heterocycloalkyl group is, similarly, fluoro, trifluoromethyl, (C ₁ -C ₄ ) -alkyl, oxo, (C ₁ -C ₄ ) -alkoxy, amino, Optionally substituted with 1 or 2 residues independently selected from the group consisting of mono- (C ₁ -C ₄ ) -alkylamino and di- (C ₁ -C ₄ ) -alkylamino, And R ⁵ is hydrogen or methyl,
A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, hydrate and / or solvate thereof. Or R ¹ is hydrogen, or _(C 1 -C ₃₎ - alkoxy, or optionally substituted with fluoro up to 3 heteroatoms _(C 1 -C ₄₎ - alkyl, or R ¹ Is a group of formula —OR ⁷ , wherein R ⁷ is up to 3 fluoro atoms, or hydroxy, (C ₁ -C ₃ ) -alkoxy, amino, mono- (C ₁ -C ₃ ) -alkylamino , Di- (C ₁ -C ₃ ) -alkylamino, azetidino, pyrrolidino, piperidino, piperazino and morpholino optionally substituted with one substituent (C ₁ -C ₄ )- Alkyl,
Wherein the azetidino, pyrrolidino, piperidino, piperazino and morpholino groups are likewise substituted with 1 or 2 residues independently selected from the group consisting of fluoro, methyl, oxo, methoxy and ethoxy Well,
R ² is hydrogen or fluoro,
R ³ is hydrogen or methyl;
R ⁴ is selected from the group consisting of (C ₁ -C ₄ ) -alkyl, phenyl and pyridyl, wherein
(I) The (C ₁ -C ₄ ) -alkyl is up to 3 fluoro atoms or (C ₁ -C ₃ ) -alkoxy, amino, mono- (C ₁ -C ₃ ) -alkylamino and di -(C ₁ -C ₃ ) -alkylamino may be substituted with one substituent selected from the group consisting of: and (ii) the phenyl and pyridyl may be fluoro, chloro, cyano, methyl and tri Optionally substituted with 1 or 2 substituents independently selected from the group consisting of fluoromethyl, and R ⁵ is hydrogen,
A compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt, hydrate and / or solvate thereof. R ¹ is hydrogen or (C ₁ -C ₄ ) -alkyl, or R ¹ is a group of formula —OR ⁷ , where R ⁷ is (C ₁ -C ₄ ) -alkyl;
R ² is hydrogen or fluoro,
R ³ is hydrogen or methyl;
R ⁴ is (C ₁ -C ₄ ) -alkyl optionally substituted with up to 3 fluoro atoms;
R ⁵ is hydrogen,
4. A compound of formula (I) according to claim 1, 2 or 3, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 4, wherein R ⁵ is hydrogen, first comprising formula (II):

(II)
[Wherein R ¹ and R ² are as defined in claims 1 to 4]
An aldehyde represented by formula (III):

(III)
[Wherein, R ⁴ is as defined in claims 1 to 4]
In the presence of an acid, an acid / base combination, and / or a dehydrating agent, and a compound of formula (IV):

(IV)
[Wherein R ¹ , R ² and R ⁴ are as defined in claims 1 to 4]
The compound represented by formula (V):

(V)
[Wherein R ³ is as defined in claims 1 to 4]
And a compound represented by the formula (IA):

(IA)
[Wherein R ¹ , R ² , R ³ and R ⁴ are as defined in claims 1 to 4]
To obtain a compound represented by
If necessary, subsequently (i) compound (IA) is separated into its individual enantiomers and / or diastereomers, preferably using chromatographic methods, and / or (ii) compound (IA) Is converted to its corresponding individual hydrate, solvate, salt and / or hydrate or solvate of the salt by treatment with a solvent and / or acid or base.   5. A compound according to any one of claims 1 to 4 for the treatment or prevention of disease.   Use of a compound according to any of claims 1 to 4 for the manufacture of a pharmaceutical composition for the treatment or prevention of cell proliferative disorders.   8. Use according to claim 7, wherein the cell proliferative disorder is cancer.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, and a pharmaceutically acceptable excipient.   10. The pharmaceutical composition according to claim 9, further comprising one or more additional therapeutic agents.   11. The pharmaceutical composition according to claim 10, wherein the additional therapeutic agent is an antitumor agent.   The pharmaceutical composition according to any one of claims 9 to 11, for treating or preventing a cell proliferative disorder.   A method for treating or preventing a cell proliferative disorder in a mammal, comprising a therapeutically effective amount of one or more compounds according to any one of claims 1 to 4 or any one of claims 9 to 11. Administering to a mammal in need thereof.   14. The method of claim 13, wherein the cell proliferative disorder is cancer.   15. The method of claim 14, wherein the cancer is breast, airway, brain, genitals, gastrointestinal tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid cancer, or distant metastasis of solid tumor.   15. The method according to claim 14, wherein the compound according to any one of claims 1 to 4 or the pharmaceutical composition according to any one of claims 9 to 11 is administered in combination with surgery or radiation therapy.